ID: 33537405
Title: Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.
Abstract: In brain, extracellular vesicles (EVs) play an essential role in the neuron-glia interface and ensure the crosstalk between the brain and the periphery. Some studies now link the pathway dysfunction of the EVs to apolipoprotein E gene variant (APOE ε4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of APOE ε4 in pre-clinical AD, we have determined levels of pathogenic, neurotrophic and inflammatory proteins in peripheral EVs (pEVs) and in plasma from cognitively impaired, no dementia (CIND) participants stratified upon the absence (APOE ε4-) or the presence (APOE ε4+ ) of the ε4 allele of APOE. Levels of 15 neurodegenerative, neurotrophic and neuroinflammatory proteins were quantified in pEVs and compared to their plasma levels from cognitively normal and CIND participants. Levels of neurotrophic and inflammatory markers were reduced in pEVs from APOE ε4+. The pentraxin-2/α-synuclein ratio measured in pEVs was able to predict AD 5 years before the onset among APOE ε4+-CIND individuals. Our findings suggest an alteration of the endosomal pathway in APOE ε4+ and that pEVs pentraxin-2/α-synuclein ratio could serve as a useful early biomarker for AD susceptibility.

ID: 34028667
Title: miR-146a Dysregulates Energy Metabolism During Neuroinflammation.
Abstract: Alzheimer's disease (AD) and other neurodegenerative diseases are characterized by chronic neuroinflammation and a reduction in brain energy metabolism. An important role has emerged for small, non-coding RNA molecules known as microRNAs (miRNAs) in the pathophysiology of many neurodegenerative disorders. As epigenetic regulators, miRNAs possess the capacity to regulate and fine tune protein production by inhibiting translation. Several miRNAs, which include miR-146a, are elevated in the brain, CSF, and plasma of AD patients. miR-146a participates in pathways that regulate immune activation and has several mRNA targets which encode for proteins involved in cellular energy metabolism. An additional role for extracellular vesicles (EVs) has also emerged in the progression AD, as EVs can transfer functionally active proteins and RNAs from diseased to healthy cells. In the current study, we exposed various cell types present within the CNS to immunomodulatory molecules and observed significant upregulation of miR-146a expression, both within cells and within their secreted EVs. Further, we assessed the effects of miR-146a overexpression on bioenergetic function in primary rat glial cells and found significant reductions in oxidative phosphorylation and glycolysis. Lastly, we correlated miR-146a expression levels within various regions of the AD brain to disease staging and found significant, positive correlations. These novel results demonstrate that the modulation of miR-146a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function in cells, thereby contributing to the progression of beta-amyloid and tau pathology in the AD brain. Multiple inflammatory stimuli can upregulate miRNA-146a expression within neurons, mixed glial cells, and brain endothelial cells, which is either retained within these cells or released from them as extracellular vesicle cargo. The upregulation of miR-146a disrupts cellular bioenergetics in mixed glial cells. This mechanism may play a critical role in the neuroinflammatory response observed during Alzheimer's disease.

ID: 34541286
Title: Effect of APOE ε4 allele on levels of apolipoproteins E, J, and D, and redox signature in circulating extracellular vesicles from cognitively impaired with no dementia participants converted to Alzheimer's disease.
Abstract: The substantial link between apolipoprotein E (APOE) ε4 allele and oxidative stress may underlie enhanced Alzheimer's disease (AD) risk. Here, we studied the impact of APOE ε4 on the level of apolipoproteins with antioxidant activities along with oxidative markers in circulating extracellular vesicles (cEVs) and plasma from cognitively impaired-not demented (CIND) individuals converted to AD (CIND-AD). Apolipoproteins E, J, and D and antioxidant response markers were determined in cEVs and plasma using immunoblotting, electrochemical examination, and spectrofluorimetry. Total antioxidant capacity and apolipoprotein D levels in cEVs, as judged by regression analysis and cognitive performance correlations, allowed us to differentiate CIND APOE ε4 carriers from controls and to predict their progression to AD 5 years later. Our findings support the pathological redox linkage between APOE ε4 and AD onset and suggest the use of cEVs oxidative signature in early AD diagnosis.

ID: 35573689
Title: Differential Effects of APOE Genotype on MicroRNA Cargo of Cerebrospinal Fluid Extracellular Vesicles in Females With Alzheimer's Disease Compared to Males.
Abstract: Multiple biological factors, including age, sex, and genetics, influence Alzheimer's disease (AD) risk. Of the 6.2 million Americans living with Alzheimer's dementia in 2021, 3.8 million are women and 2.4 million are men. The strongest genetic risk factor for sporadic AD is apolipoprotein E-e4 (APOE-e4). Female APOE-e4 carriers develop AD more frequently than age-matched males and have more brain atrophy and memory loss. Consequently, biomarkers that are sensitive to biological risk factors may improve AD diagnostics and may provide insight into underlying mechanistic changes that could drive disease progression. Here, we have assessed the effects of sex and APOE-e4 on the miRNA cargo of cerebrospinal fluid (CSF) extracellular vesicles (EVs) in AD. We used ultrafiltration (UF) combined with size exclusion chromatography (SEC) to enrich CSF EVs (e.g., Flotillin+). CSF EVs were isolated from female and male AD or controls (CTLs) that were either APOE-e3,4 or -e3,3 positive (n = 7/group, 56 total). MiRNA expression levels were quantified using a custom TaqMan™ array that assayed 190 miRNAs previously found in CSF, including 25 miRNAs that we previously validated as candidate AD biomarkers. We identified changes in the EV miRNA cargo that were affected by both AD and sex. In total, four miRNAs (miR-16-5p, -331-3p, -409-3p, and -454-3p) were significantly increased in AD vs. CTL, independent of sex and APOE-e4 status. Pathway analysis of the predicted gene targets of these four miRNAs with identified pathways was highly relevant to neurodegeneration (e.g., senescence and autophagy). There were also three miRNAs (miR-146b-5p, -150-5p, and -342-3p) that were significantly increased in females vs. males, independent of disease state and APOE-e4 status. We then performed a statistical analysis to assess the effect of APOE genotype in AD within each sex and found that APOE-e4 status affects different subsets of CSF EV miRNAs in females vs. males. Together, this study demonstrates the complexity of the biological factors associated with AD risk and the impact on EV miRNAs, which may contribute to AD pathophysiology.

ID: 36540894
Title: Evaluation of blood-based, extracellular vesicles as biomarkers for aging-related TDP-43 pathology.
Abstract: Limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. To date, LATE-NC is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of extracellular vesicle (EVs) protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. TDP-43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE (n = 22). Quantified TDP-43 concentrations were compared to the cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE-NC (n = 42). TDP-43 was significantly elevated in plasma ADEVs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in EV-depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between EV TDP-43 levels with cognition-based variables, sex, and APOE carrier status. Blood-based EVs, specifically measuring TDP-43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.

ID: 38416841
Title: APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.
Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

ID: 39307629
Title: The multiple roles of chronic stress and glucocorticoids in Alzheimer's disease pathogenesis.
Abstract: Chronic stress and the accompanying long-term elevation of glucocorticoids (GCs), the stress hormones of the body, increase the risk and accelerate the progression of Alzheimer's disease (AD). Signatures of AD include intracellular tau (MAPT) tangles, extracellular amyloid β (Aβ) plaques, and neuroinflammation. A growing body of work indicates that stress and GCs initiate cellular processes underlying these pathologies through dysregulation of protein homeostasis and trafficking, mitochondrial bioenergetics, and response to damage-associated stimuli. In this review, we integrate findings from mechanistic studies in rodent and cellular models, wherein defined chronic stress protocols or GC administration have been shown to elicit AD-related pathology. We specifically discuss the effects of chronic stress and GCs on tau pathogenesis, including hyperphosphorylation, aggregation, and spreading, amyloid precursor protein (APP) processing and trafficking culminating in Aβ production, immune priming by proinflammatory cytokines and disease-associated molecular patterns, and alterations to glial cell and blood-brain barrier (BBB) function.

ID: 40700291
Title: Potential Biological and Genetic Links Between Dementia and Osteoporosis: A Scoping Review.
Abstract: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions. Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone-brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis-dementia pathophysiology. Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study.

ID: 40882623
Title: Selenized neural stem cell-derived exosomes: A neotype therapeutic agent for traumatic injuries of the central nervous system.
Abstract: Oxidative damage and neuroinflammation are the key features of central nervous system (CNS) injury. Inspired by the neuroprotective properties of neural stem cell-derived exosomes (NExo) and the reactive oxygen species (ROS) scavenging ability of selenium, we develop an advanced NExo bearing ultrasmall nano-selenium (∼3.5 nm) via lipid-mediated nucleation (SeNExo). In addition to maintaining the biological components of NExo, the resulting SeNExo exhibits a Se-O bond that dramatically enhances its ROS-scavenging performance. SeNExo penetrates the blood-brain barrier (BBB) via the apolipoprotein E and prolow-density lipoprotein receptor-related protein 1 (APOE_LRP-1) interaction. Through proteomics, microRNA (miRNA) omics, and single-nucleus RNA sequencing, we find that SeNExo can alleviate neuronal apoptosis, restore glia homeostasis, and remodel glia-neuron networks. Therefore, SeNExo confers potent therapeutic benefits, significantly reducing cerebral lesions in a murine traumatic brain injury model. Even extending to a murine spinal cord injury model, SeNExo promotes locomotory recovery, further supporting SeNExo as a neotype and a promising therapeutic agent for treating traumatic CNS injury.

ID: 40933257
Title: Supplementation with fish oil reduces αβ 42 burden and shifts αβ precursor protein processing toward non-amyloidogenic pathways in a rat model of hyperglycaemic Alzheimer's disease.
Abstract: This study examines the influence of fish oil on brain amyloidogenesis in hyperglycaemic Alzheimer's disease animal models, emphasising the potential of omega-3 fatty acids in fish oil to prevent the development of Alzheimer's disease. Thirty males of Wistar rats were divided into five groups: 1) control rats (NS); 2) rats supplemented with 3 g/kg of fish oil (NS+FO3); 3) rats injected via intraperitoneal (i.p) with Streptozotocin-Lipopolysaccharide (STZ-LPS); 4) rats injected with STZ-LPS (i.p) and supplemented with 1 g/kg of fish oil (STZ-LPS+FO1), and 5) rats injected with STZ-LPS (i.p) and supplemented with 3 g/kg of fish oil (STZ-LPS+FO3). The cerebral brain was extracted for examination, and the αβ precursor protein (APP) level was measured using an immunoassay kit, while αβ 42 expression was evaluated using immunohistochemistry staining. Brain amyloidosis-related genes were quantified using real-time Polymerase Chain Reaction (PCR). The results revealed that fish oil supplementation significantly increased APP levels and reduced αβ 42 accumulations in STZ-LPS rats. Moreover, the Apolipoprotein E, ε4 isoform (ApoE-4) and Beta-site APP-cleaving enzyme 1 (Bace-1) genes were downregulated while the Low-density lipoprotein receptor-related protein 1 (Lrp-1) gene was upregulated in STZ-LPS rats treated with fish oil, thereby elucidating the impact of fish oil on diminishing αβ buildup in the brain. Therefore, this study contributes to a growing body of evidence supporting dietary interventions as adjunctive strategies for the prevention or delay of Alzheimer's disease progression in metabolic dysfunction.

ID: 40972159
Title: Targeting the blood-brain barrier with lipoprotein-mimicking nanoparticles loaded with flurbiprofenaxetil and coated with apolipoprotein E3.
Abstract: In previous studies, it has been demonstrated that lipoprotein-mimicking nanoparticles with a solid lipid core of cholesteryl oleate, a lecithin coating and adsorptively bound apolipoprotein E3 (ApoE) may serve as a potential vehicle for drug delivery to the central nervous system. In this study, the impact of drug characteristics, particularly lipophilicity, was evaluated to achieve a stable incorporation of model drugs into these lipid-based nanoparticles (LNPs). This study explored the lipophilicity of flurbiprofen, a potential drug in the treatment of Alzheimer's disease (AD), and its prodrug flurbiprofenaxetil across varying pH levels. Our findings highlight how flurbiprofen's lipophilicity was influenced by its protonation state, affecting its incorporation into LNPs and consequently its release behaviour under physiological conditions, while flurbiprofenaxetil showed minimal variations due to its chemical structure. We also investigated the interaction between lipoprotein mimicking nanoparticles and primary porcine brain capillary endothelial cells to improve drug delivery across the blood-brain barrier (BBB). Permeation studies indicated that modification with ApoE enhanced the bidirectional permeability of LNPs across the BBB through receptor-mediated transcytosis. Furthermore, we demonstrated and identified the uptake mechanism involving the low density lipoprotein receptor-related protein 1 (LRP1), allowing these LNPs to be recognized by the same receptors as endogenous lipoproteins. Overall, these findings highlight the potential of ApoE modified LNPs as a promising strategy for targeted drug delivery to the brain.

ID: 40993829
Title: Reduced synaptic vesicle protein 2A in extracellular vesicles and brains of Alzheimer's disease: associations with Aβ, tau, synaptic proteins and APOE ε4.
Abstract: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary Tangles and synaptic dysfunction. The aim of this study was to map the distributions of synaptic vesicle protein 2A (SV2A) and other synaptic proteins in the brain and the brain-derived extracellular vesicles (BDEVs) of AD patients, analyze their associations with Aβ, tau, and the apolipoprotein E (APOE) ε4 allele, and investigate the biological role of SV2A. Mass spectrometry-based proteomics of BDEVs and immunohistochemistry staining were conducted on postmortem brain samples from 57 AD patients and 48 nondemented controls. The levels of SV2A, synaptophysin (SYP), and other synaptic proteins in the brain tissues and the BDEVs, and their associations with Aβ, tau (phospho-tau and Braak stages), other proteins and the APOE ε4 allele, were analyzed. SV2A levels were significantly lower in AD patients than in nondemented controls, particularly in the hippocampus and entorhinal cortex. APOE ε4 carriers presented further reductions in SV2A levels compared with noncarriers. The SV2A levels in BDEVs and brain tissues were positively correlated with SYP levels and negatively correlated with Aβ and phospho-tau levels. Reductions in SV2A were associated with decreased levels of other synaptic proteins, such as synaptotagmins, GAP43, and SNAP25. SV2A emerged as a central hub with interactions with proteins from subnetworks related to synaptic vesicle formation and fusion. SV2A levels in brain tissues and BDEVs are reduced in AD patients, particularly in those carrying the APOE ε4 allele, and are correlated with Aβ and tau pathologies. SV2A may serve as a valuable biomarker for monitoring synaptic dysfunction and progression in AD.

ID: 41089833
Title: Therapeutic potential of extracellular vesicles derived from Platycladus Orientalis leaf in treating anxiety, depression, and insomnia.
Abstract: Extracellular vesicles (EVs) mediate intercellular communication by transferring bioactive molecules. While animal-derived EVs are well studied, plant-derived EVs (plant-EVs) are emerging as stable, low-immunogenic nanocarriers with therapeutic potential. Platycladus orientalis (L.) Franco, used in traditional medicine, contains neuroactive compounds. This study evaluated the effects of P. orientalis leaf-derived EVs in rodent models of anxiety, depression, and insomnia. EVs were isolated by differential ultracentrifugation, characterized by electron microscopy and nanoparticle tracking analysis, and their bioactive components identified by GC -MS. Uptake was assessed in PC12 cells. Behavioral and biochemical effects were tested in mice subjected to chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and para-chlorophenylalanine (PCPA)-induced insomnia. Key outcomes included social interaction, sucrose preference, Morris water maze performance, sleep parameters, neurotransmitter levels (5-HT, GABA), and inflammatory markers. P. orientalis EVs exhibited bilayer vesicle morphology (∼100 nm) and contained abundant volatile compounds, particularly α-pinene. They were internalized by PC12 cells and reduced corticosterone-induced injury. In vivo, intranasal EV administration alleviated anxiety-like behaviors in CRS mice, restored sucrose preference and cognition in CUMS mice, and improved sleep onset and duration in PCPA-induced insomnia. Across models, EVs normalized serum and hippocampal 5-HT and GABA levels, reduced pro-inflammatory cytokines (TNF-α, IL-6), and increased TGF-β expression. P. orientalis leaf-derived EVs exert significant anxiolytic, antidepressant, and soporific effects through multimodal mechanisms involving neurotransmitter regulation and anti-inflammatory activity. Intranasal administration offers an effective strategy to bypass the blood -brain barrier, supporting the translational potential of plant-EVs as novel therapeutics for psychiatric disorders.

ID: 41090985
Title: The Intranasal Administration of Transferrin-Loaded Extracellular Vesicles Enhances Remyelination.
Abstract: Oligodendrocytes (OLs), the myelinating glial cells of the central nervous system (CNS), are impaired in demyelinating diseases such as multiple sclerosis (MS). OL loss is characterized by inflammation, immune cell activity, and a failure of remyelination due to oligodendrocyte dysfunction and death, ultimately leading to demyelination and axonal damage. Given their central role in maintaining CNS integrity, therapeutic strategies aimed at protecting or restoring OL function are essential. Moreover, the limited permeability of the blood-brain barrier to many therapeutic compounds remains a major challenge, highlighting the need for innovative delivery approaches. Among these, the intranasal (IN) route has emerged as a promising noninvasive strategy for targeting the CNS. Within this therapeutic framework, Transferrin (Tf), a glycoprotein involved in iron homeostasis, has been shown to promote both developmental myelination and remyelination by redistributing and delivering iron, an essential cofactor for OL maturation and oxidative metabolism. In parallel, extracellular vesicles (EVs) have gained increasing attention as mediators of intercellular communication and potential drug delivery vehicles to the brain, offering advantages such as minimal immunogenicity, efficient cellular uptake, and cargo protection from degradation. In this review, the potential of EVs as biological carriers of molecules to promote remyelination is discussed, with a particular focus on Tf delivered via the intranasal route, as well as the cellular mechanisms underlying this internalization.

ID: 41094553
Title: Extracellular vesicles derived from menstrual blood-derived mesenchymal stem cells suppress inflammatory atherosclerosis by inhibiting NF-κB signaling.
Abstract: Numerous studies have highlighted the beneficial effects of mesenchymal stem cells (MSCs) in various inflammatory disorders. However, the regulatory role of MSCs in inflammatory atherosclerosis and the molecular mechanisms underlying their anti-inflammatory properties have largely remained elusive. Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) released by menstrual blood-derived mesenchymal stem cells (MenSCs). An ApoE knockout atherosclerotic animal model was employed to investigate the regulatory effect of MenSC-EVs on inflammatory atherosclerosis. miRNA microarray screening analyses were conducted to identify potential effectors in MenSC-EVs that play a key role in the suppression of atherosclerosis mediated by the EVs. We demonstrated the remarkable potential of MenSC-EVs in alleviating atherosclerosis through the NF-κB signaling pathway. miR-574-5p serves as a crucial effector molecule transported by MenSC-EVs, suppressing endothelial inflammation and promoting nitric oxide production. This regulation contributes to the attenuation of atherosclerosis by regulating the abundance of c-Rel. The miR-574-5p/c-Rel axis shows significant clinical relevance to atherosclerosis. This study reveals that the engineering of EVs derived from MenSCs holds significant promise as a strategic clinical approach for addressing inflammatory atherosclerosis.

ID: 41102844
Title: Intranasal delivery of DPSC-derived small extracellular vesicles-encased phloroglucinol attenuates non-motor and motor deficits and promotes neurogenesis in an in vivo rat model of Parkinson's disease.
Abstract: Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron degeneration in the substantia nigra pars compacta (SNpc) driven by oxidative stress, inflammation, and impaired neurogenesis. Phloroglucinol, a polyphenolic antioxidant, has demonstrated neuroprotective effects in PD models but suffers from limited clinical applicability due to poor blood-brain barrier (BBB) permeability. Small extracellular vesicles (sEV) derived from dental pulp stem cells (DPSCs) exhibit neuroprotective and immunomodulatory properties and serve as promising vehicles for targeted drug delivery across the BBB. This study aimed to evaluate the therapeutic efficacy of intranasally administered sEV-encased phloroglucinol (sEV-Phl) in a chronic MPTP rat model of PD. DPSC-derived sEV were isolated via density gradient ultracentrifugation and characterized using Transmission Electron Microscopy (TEM), Dynamic-Light-Scattering (DLS), and CD marker expression. Phloroglucinol was encased in sEV (sEV-Phl) using sonication. Antioxidant properties were tested in vitro using an H2DCF.DA assay in SH-SY5Y cells exposed to 6-OHDA. Chronic MPTP-treated male Wistar rats received intranasal sEV-Phl, with motor and non-motor behaviours evaluated up to 4-weeks post-MPTP treatment. TH-positive neurons, neurogenesis (Ki67, BrdU and FOXA2), lipid-peroxidation, and neurotransmitter-levels were analyzed. sEV biodistribution was tracked via near-infrared imaging and localization in neuronal and glial cells was confirmed with PKH-26 labelling, with confocal-imaging further verifying localization in neuronal and glial cells. TNF-α expression was assessed as a marker of neuroinflammation. sEV displayed high purity and homogeneity. sEV-Phl significantly reduced oxidative stress both in vitro and in vivo, as indicated by decreased ROS and lipid peroxidation levels. sEV-Phl treated MPTP rats demonstrated marked improvement in motor and non-motor behaviours compared to MPTP rats. Immunohistochemical analysis revealed increased TH-positive neurons and enhanced neurogenesis in the SNpc of sEV-Phl-treated animals. Biodistribution studies confirmed efficient midbrain targeting of sEV, which were localized to dopaminergic-neurons, astrocytes and microglia. sEV-Phl also significantly reduced TNF-α expression, indicating decreased neuroinflammation. This study provides the first instance of using DPSC-derived sEV as a delivery vehicle for phloroglucinol in a PD model. sEV-Phl demonstrated significant neuroprotective-effects, enhanced DA-neuron survival and neurogenesis, and reduced neuroinflammation. Intranasal delivery of sEV-Phl represents a promising non-invasive therapeutic strategy for PD, offering a dual benefit of antioxidative and neurogenic support.

ID: 41140213
Title: The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.
Abstract: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.

ID: 41294837
Title: Neuronal Enriched Extracellular Vesicle miR-122-5p as a Potential Biomarker for Alzheimer's Disease.
Abstract: Alzheimer's disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration.

ID: 41310241
Title: Advances in Intranasal Delivery of Exosomes for Central Nervous System Disorders.
Abstract: Central nervous system disorders are major global health challenges that contribute to significant morbidity and mortality. Traditional therapeutic strategies often face substantial limitations, primarily due to the blood-brain barrier, which restricts the delivery of pharmacological agents to the brain and consequently affects treatment effectiveness. In recent years, in order to enhance the efficacy of the central nervous system treatments, exosome-based approaches have gained interest. Exosomes, small extracellular vesicles (30-150 nm) secreted by cells, present a feasible therapeutic strategy due to their ability to cross the blood-brain barrier and transport bioactive molecules. Reflecting the traits of their parent cells (e.g., glioma stem cells and glioblastoma multiforme), exosomes can be isolated from body fluids, which enhances their clinical applicability. Additionally, intranasal delivery provides a non-invasive method to administer exosomes, using the olfactory and trigeminal nerve pathways to bypass the blood-brain barrier and directly target the brain. This method shows great promise in enhancing therapeutic efficacy for CNS disorders. However, challenges such as rapid mucociliary clearance, enzymatic degradation, and limited bioavailability reduce efficacy. Advances in exosome engineering, nanocarrier systems, and novel delivery devices are under investigation to mitigate these constraints. However, clinical translation requires further research to guarantee safety, consistency, and scalability. In this context, intranasal exosome delivery holds considerable promise as a non-invasive strategy for central nervous system disorder treatment, contingent on overcoming the current biological and technical barriers.

ID: 41503985
Title: The Role of Exosomes as Endogenous Nanocarriers for Targeted Drug Delivery: Isolation, Engineering, and Clinical Progress in Neurological and Other Diseases.
Abstract: Exosomes are extracellular vesicles that carry a variety of biomolecules, including nucleic acids, proteins, and lipids, and they play a vital role in intercellular communication. These endogenous carriers offer several advantages over conventional nanocarriers, such as liposomes. These advantages include high biocompatibility, low immunogenicity, and the ability to cross biological barriers such as the blood-brain barrier, making them a promising platform for targeted drug delivery. In this review, we systematically summarize the biological characteristics of exosomes, methods for their isolation and purification, strategies for drug loading (including endogenous and exogenous approaches), and surface engineering techniques (such as genetic engineering and chemical modification) to enhance targeting and therapeutic efficacy, based on a comprehensive PubMed literature search. We particularly focus on the modification of engineered exosomes as drug delivery systems in various clinical contexts, covering multiple diseases including cancer, diabetes, neurological diseases, cardiovascular diseases, and tissue repair. Administration routes include oral, subcutaneous, intranasal, and intravenous delivery. While exosomes have shown promise in preclinical studies, challenges remain in terms of large-scale production, standardized isolation, drug loading efficiency, and safety evaluation. Herein, we aim to provide a theoretical foundation and suggest future directions for developing exosomes as a next-generation drug delivery platform.

ID: 41566550
Title: Plasma extracellular vesicles from APOE3 Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease.
Abstract: The PSEN1E280A mutation causes autosomal dominant Alzheimer's disease (ADAD) with predictable onset, enabling presymptomatic studies. Extracellular vesicles (EVs) are emerging biomarkers of cognitive decline, but their role in early ADAD is unclear. The rare apolipoprotein E (APOE3) Christchurch (APOE3Ch) variant delays disease onset, yet its effect on EVs is unknown. We analyzed plasma EVs from mild cognitive impairment (MCI) and non-MCI PSEN1E280A-APOE3 carriers and non-MCI PSEN1E280A-APOE3Ch carriers using flow cytometry, proteomics, and co-culture assays. APOE3Ch-EVs showed reduced vascular activation and inflammatory cargo linked to β-catenin signaling, higher apoE levels, and enrichment in lipid-loaded EVs. They mimicked the protective effect of recombinant ApoE3Ch on endothelial integrity by restoring β-catenin nuclear localization. In contrast, EVs from non-MCI PSEN1E280A-APOE3 carriers displayed vascular and inflammatory signatures associated with poorer cognition and detrimental astrocyte-endothelium effects. These findings highlight APOE3Ch-EVs as modulators of vascular and inflammatory pathways with biomarker and therapeutic potential in ADAD.

ID: 41678912
Title: Exosomal miR-10b derived from protocatechuic acid-treated efferocytic macrophages inhibits endothelial inflammation by targeting MAP3K7/β-TrCP/NF-κB signaling pathway.
Abstract: Protocatechuic acid (PCA), a natural compound found in a variety of Chinese herbal medicines and plant foods, has been documented to inhibit atherosclerosis partially by reducing inflammation burden in arterial endothelial cells. Interestingly, in vitro studies showed that PCA at physiologically reachable concentrations does not affect inflammation burden in TNF-α-stimulated aortic endothelial cells, whereas it increases the content of exosomal miR-10b secreted by macrophages that have engulfed apoptotic cells (efferocytic macrophages). This study was aimed at investigating whether the in vivo anti-inflammatory effect of PCA in arterial endothelial cells was due to the uptake of efferocytic macrophage exosomal miR-10b. A transwell co-culture system of aortic endothelial cells with efferocytic macrophages was used to evaluate the effect of PCA on NF-κB-mediated inflammation in aortic endothelial cells. An inhibitor of exosome secretion, GW4869, was applied to confirm the role of exosomes played in the anti-inflammatory effect of PCA. The aortic endothelial cells were administrated with exosomes isolated from PCA-treated efferocytic macrophages or miR-10b mimic or antagomir to ascertain the role of miR-10b in downregulating inflammation effect of PCA. Bioinformatics analyses, loss-of- and gain-of-function assays and luciferase reporter gene assays were performed to identify targeting relationship between miR-10b and mitogen-activated protein kinase kinase kinase 7 (MAP3K7)/β-transducin repeat-containing protein (β-TrCP). Besides, Apoe-/- mice with advanced atherosclerotic plaques were subjected to intragastric administration of PCA and intraperitoneal injection of GW4869. The miR-10b/MAP3K7/β-TrCP/NF-κB signaling pathways and inflammation indicators were determined in vivo. PCA at physiologically reachable concentrations inhibited NF-κB-mediated inflammation in TNF-α-stimulated aortic endothelial cells co-cultured with efferocytic macrophages, in which treatment of GW4869 reversed this effect. Exosomes isolated from PCA-treated efferocytic macrophages inhibited inflammation and increased miR-10b levels in aortic endothelial cells. Mechanistically, exosomal miR-10b post-transcriptionally repressed MAP3K7 and β-TrCP, both of which promote NF-κB activation. Knockdown of Map3k7 and Btrc with siRNA in aortic endothelial cells abolished the inhibitory effects of exosomes isolated from PCA-treated efferocytic macrophages on NF-κB-mediated inflammation. Consistently, oral administration of PCA increased miR-10b level and inhibited Map3k7 and Btrc mRNA expression as well as inflammation in aortic endothelial cells in Apoe-/- mice, all of which were abrogated by GW4869 co-treatment. Our current findings suggest that PCA could transfer exosomal miR-10b from efferocytic macrophages to endothelial cells and thus inhibit NF-κB-mediated inflammation in arterial endothelial cells through repressing MAP3K7 and β-TrCP, two new targets of miR-10b.

ID: 41934727
Title: Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.
Abstract: Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways.

ID: 41970527
Title: A potential multimodal biomarker - cognitive signature associated with the conversion from subjective cognitive decline to mild cognitive impairment.
Abstract: The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI). A cytokine panel and the levels of Aβ1-42 were quantified in both cEVs and serum from a longitudinally followed cohort of elderly with SCD, using mesoscale and Luminex technologies. We investigated associations with Aβ burden, cognitive performance, APOE ε4 allele status, and the likelihood of conversion to MCI. In SCD patients, the concentrations of Aβ1-42 and macrophage-colony stimulating factor (M-CSF) were higher, respectively, in cEVs and serum. No difference was observed for fraktaline, interleukin (IL)-4, IL-13, interferon gamma (IFN-γ), and sCD40L in either cEVs or serum between SCD and control patients. Based on receiver operating characteristic curve analysis, regression modeling, and correlations with cognitive performance, M-CSF levels in serum effectively distinguished individuals with SCD who converted to MCI from those who remained stable. Interestingly, combining M-CSF and cEVs Aβ1-42 with the Rey Auditory Verbal Learning Test (RAVLT) cognitive scores provided an excellent classification for SCD converted to MCI up to 2 years prior to clinical diagnosis. Our findings support the potential value of integrating serum M-CSF levels with RAVLT performance and cEVs Aβ1-42 concentrations into a multimodal biomarker panel for longitudinal monitoring of progressive neurocognitive impairment.

ID: 41989517
Title: Exosomes in Alzheimer's disease: neuroinflammation mitigation via immune modulation and inflammatory pathway targeting.
Abstract: Alzheimer’s disease (AD) progression is tightly linked to neuroinflammation driven by central-peripheral immune imbalance, with microglial/astrocytic activation, blood-brain barrier disruption, and cytokine dysregulation forming a vicious cycle. Exosomes, as nanoscale extracellular vesicles, emerge as potent modulators by crossing the blood-brain barrier and delivering functional cargos (miR-146a, miR-124, TREM2, IL-10) to target immune and neuronal cells. They induce M2 microglial polarization, inhibit A1 astrocyte transformation, and balance Treg/Th17 subsets, while suppressing NF-κB and NLRP3 inflammasome pathways to reduce pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and elevate anti-inflammatory IL-10. Additionally, exosomes enhance Aβ/tau clearance via promoting phagocytosis and autophagy, and repair the blood-brain barrier to mitigate peripheral immune infiltration. Derived from MSCs, immune cells, or traditional Chinese medicines, exosomes exhibit low immunogenicity and high biocompatibility, with preclinical and pilot clinical data confirming 30%–50% improvement in cognitive scores and 40%–60% reductions in cerebrospinal fluid IL-1β, TNF-α, and IL-6 levels in AD models and patients. These findings highlight exosomes as a multitargeted strategy to ameliorate neuroinflammation and halt AD neurodegeneration.

ID: 41995755
Title: Mitochondrial-Immune Dysfunction in MS: Therapeutic Potential of EV-Mediated Transfer.
Abstract: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system. In this disease, mitochondrial dysfunction contributes to neurodegeneration, axonal loss, and progressive disability. Extracellular vesicle (EV)-mediated mitochondrial transfer has emerged as a promising cell-free strategy to restore mitochondrial homeostasis and modulate immune responses within the CNS. Preclinical studies, particularly in experimental autoimmune encephalomyelitis models, demonstrate that EV-based delivery of mitochondrial cargo improves cellular bioenergetics. In parallel, this approach reduces oxidative stress and neuroinflammation while supporting remyelination and neuroprotection. This review summarizes the mechanistic rationale, current preclinical evidence, and future translational perspectives of EV-mediated mitochondrial therapy in MS.

ID: 42031321
Title: Co-aggregation of amyloidogenic proteins in age-related neurodegenerative diseases.
Abstract: Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as microtubule-associated protein-Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's aggregation dynamics and toxicity. This review critically examines the mechanistic and pathological underpinnings of heterotypic protein co-aggregation, integrating biophysical, cellular, animal, and human data. This review further proposes a conceptual framework that views neurodegeneration as a network of interacting misfolded proteins shaped by age-related changes in lipid membranes, redox balance, proteostasis, and genetic factors. Emphasis is placed on translational opportunities: co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and emerging multi-targeted therapies including immunotherapy, proteostasis modulators, and autophagy-inducing chimeras. This review also discusses the clinical implications of co-pathology in mixed dementias and overlapping disorders. It is therefore time to move beyond the classical one protein-one disease paradigm and embrace models that explicitly incorporate heterotypic co-aggregation, mixed pathologies, and shared vulnerability pathways across age-related disorders. By reframing co-aggregation as a central pathogenic mechanism, this review highlights the need for diagnostics and therapeutics that address the interconnectivity of protein misfolding in the ageing brains.

ID: 42060826
Title: When Viruses Talk through Extracellular Vesicles: a New Perspective on Sars-Cov-2-Induced Neurodegeneration.
Abstract: SARS-CoV-2 infection is linked to persistent neurological symptoms Post-Acute Sequelae SARS-CoV-2 (neuro-PASC) and elevated risk of neurodegenerative disease, but molecular events connecting acute viral injury to long-term CNS dysfunction remain unclear. Here, we advance a perspective that Extracellular Vesicles (EVs) act as active mediators bridging SARS-CoV-2 infection and neurodegenerative processes. As nanoscale messengers capable of crossing the blood-brain barrier, EVs can transmit post-viral signals and orchestrate multi-target gene regulation in recipient cells through their microRNA (EV-miRNA) cargo. Our integrative analysis suggests that EV-miRNAs dysregulated in acute COVID-19, Alzheimer's Disease (AD), and Parkinson's Disease (PD) converge on pathways governing neurovascular integrity, redox and metabolic homeostasis, and neuronal proteostasis. We propose that sustained dysregulation of these interconnected modules-driven by EV-mediated signalling-may underlie the perpetuation of neuro-PASC and accelerate neurodegeneration in susceptible individuals. Viewing EVs as mechanistic agents that both transmit and amplify pathogenic cues reframes them as actionable targets for intervention and risk stratification. This perspective calls for translational frameworks that leverage EVs to illuminate, predict, and modify the trajectory of post-viral neurodegeneration.

ID: 42113482
Title: Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria.
Abstract: Mitochondria-targeted therapies hold great promise for treating metabolic syndrome, neurodegeneration, and cancers associated with mitochondrial dysfunction or genetic mutations. However, its advancement is significantly limited by the lack of effective and biocompatible targeted delivery systems. Here, we introduce mitofusin-decorated extracellular vesicles (MFNEVs) as a natural-sourced nanoplatform for efficient mitochondrial delivery of various cytoplasm-sensitive macromolecular cargos. The surface-displayed mitofusin proteins MFN1 and MFN2 direct MFNEVs to localize to mitochondria, as confirmed by confocal imaging and gel electrophoresis analysis. In both in vitro and in vivo models, siRNA-loaded MFNEVs effectively reduce the expression of mitochondrial DNA-encoded genes. Moreover, sgRNA-loaded MFNEVs can achieve CRISPR-based mitochondrial gene editing, resulting in a decreased mitochondrial DNA content. Mechanistic studies further reveal that the delivery is facilitated by the cooperation of the mitochondrial fusion machinery. These findings establish the feasibility and versatility of MFNEVs as a promising delivery solution for mitochondrial therapeutics.

ID: 42120733
Title: Brain endothelial cell-derived extracellular vesicles (c-BEEVs) as a promising biomarker for brain vascular pathology and cognitive decline.
Abstract: Accurate measurement of brain vascular pathology is essential for understanding its role in cognitive aging. Here we classified participants using the amyloid-tau-neurodegeneration framework in a multicenter cohort and identified cerebrospinal fluid brain endothelial-derived small extracellular vesicles (c-BEEVs) as a sensitive biomarker, which correlated with vascular risk factors and the severity of small-vessel disease. c-BEEVs showed high diagnostic performance for vascular cognitive impairment and, when combined with p-tau181, effectively distinguished vascular cognitive impairment from Alzheimer's disease. In individuals with mixed Alzheimer's disease and vascular pathology, c-BEEVs were the earliest indicators of abnormalities. It predicted cognitive decline in participants without p-tau181 pathology. To investigate the mechanistic role of c-BEEVs, we established a hypertension mouse model with elevated c-BEEVs and cognitive deficits. Brain endothelial-specific knockdown of extracellular vesicle secretion alleviated cognitive and synaptic impairment. These findings position c-BEEVs as a promising biomarker for brain vascular pathology and highlight their role in neurovascular dysfunction.

ID: 42121153
Title: The lung-brain axis mediates the neuroprotective effects of nasally administered L. salivarius and its EV-delivered metabolite in vascular dementia.
Abstract: Neuroinflammation and impaired barrier function are two prominent pathological mechanisms contributing to cognitive impairment in patients with vascular dementia (VaD). Currently, effective treatments for VaD remain limited, underscoring the clinical significance of developing novel, multi-targeted therapeutic strategies. In recent years, more and more studies have shown the connection between lung and brain, so we used nasal administration of probiotics to observe the improvement of cognitive function in VaD rats. Because the safety of the organism is uncertain, the study develop a bacterial extracellular vesicles (EVs) drug delivery system that delivers the key bioactive metabolite asperuloside (ASP) by modulating the microbiota-lung-brain axis, aiming to improve brain targeting and therapeutic outcomes. The results show that nasal administration of L. salivarius significantly ameliorated cognitive impairment, mitigated neuroinflammation, restored blood-brain barrier and lung barrier function, and modulated lung flora in VaD rats. Metabolomics analysis identified ASP as the principal active metabolite, although its efficacy as a standalone agent was constrained. The EA system effectively facilitated ASP delivery to brain tissue, yielding neuroprotective and barrier-repair effects. Collectively, our study shows that L. salivarius can modulate the pathophysiological processes of VaD via the "microbiota-lung-brain axis." Its EVs serve as effective vehicles for delivering active metabolites, offering a novel integrated therapeutic approach for VaD involving microbial metabolism delivery.

ID: 42161925
Title: O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.
Abstract: Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.

ID: 42206051
Title: Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau pathology, and sustained neuroinflammation. Increasing evidence indicates that dysregulated lipid metabolism is not merely a metabolic disturbance but a critical modulator of inflammatory responses driving AD pathogenesis. The brain, one of the most lipid-enriched organs, relies on tightly controlled lipid homeostasis to maintain neuronal function and synaptic integrity. Alterations in fatty acid composition, apolipoprotein E (ApoE) isoforms, lipoprotein lipase activity, and lipid-derived signaling mediators profoundly reshape microglial activation states and inflammatory cascades. Obesity, insulin resistance, and gut microbiota dysbiosis further exacerbate systemic and central lipid imbalance, amplifying neuroinflammatory signaling through cytokine networks and blood-brain barrier disruption. Notably, polyunsaturated fatty acids and lipid mediators exert dual immunomodulatory effects, influencing β-amyloid aggregation, oxidative stress, and microglial polarization. This review synthesizes recent advances in understanding how lipid metabolism modulates neuroinflammation and microglia-neuron crosstalk in AD, highlighting emerging therapeutic strategies targeting lipid-inflammation axes as promising avenues for disease modification.

ID: 42212852
Title: LRP1 Activation Promotes Metabolic Reprogramming and Mrc1 Expression to Attenuate LPS-Induced Cognitive Deficits: An Integrated Omics Analysis.
Abstract: Central insulin resistance and neuroinflammation act as synergistic drivers in the pathogenesis of cognitive decline. While the low-density lipoprotein receptor-related protein 1 (LRP1) is known to maintain blood-brain barrier integrity, its capacity to decouple the inflammation-metabolism axis remains underexplored. This study investigates whether activation of LRP1 can ameliorate LPS-induced cognitive deficits by recalibrating cerebral glucose metabolism. We utilized an integrative approach combining behavioral phenotyping with targeted metabolomics and transcriptomics to dissect the neuroprotective mechanism of SP16, a selective LRP1 agonist. Cognitive dysfunction was modeled in mice via intracerebroventricular (i.c.v) LPS administration, followed by systemic intervention with intraperitoneally (i.p) injected SP16. SP16 treatment preserved cognitive function and prevented neuronal structural atrophy against the LPS injection. Mechanistically, LRP1 activation did more than suppress inflammation; it functionally modulated hippocampal insulin sensitivity and re-established redox homeostasis. Crucially, metabolomic profiling highlighted a restoration of glycolytic flux, centered on the normalization of fructose-1,6-bisphosphate (FBP) levels. This metabolic reprogramming coincided with the upregulation of the M2-like reparative marker, Mrc1. Our findings identify LRP1 as a regulator that bridges metabolic health and immune resolution. By enforcing a metabolic shift via the FBP node, SP16 effectively guides microglia from a pro-inflammatory state toward tissue repair. Thus, honing in on SP16-mediated metabolic reprogramming presents an opportunity for a therapeutic intervention against neuroinflammation-associated cognitive impairment, offering a more nuanced alternative to broad-spectrum anti-inflammatories.

ID: 42251801
Title: CD146 extracellular vesicles accumulate at atherosclerotic lesions, reducing inflammation and atheroma burden.
Abstract: Atherosclerosis remains the most important cause of death worldwide despite an extensive therapeutic arsenal. We previously showed that CD146, an adhesion molecule expressed by endothelial cells, is harbored by macrophages in atherosclerotic plaque and allows to reduce CCL5 and subsequent inflammation. As extracellular vesicles may serve as potential clinical delivery devices, we hypothesized that CD146 extracellular vesicles injection could be atheroprotective. We generated and purified extracellular vesicles from mouse endothelial cells deleted or not with CD146. In vitro stimulation of macrophages with CD146 extracellular vesicles induced macrophage polarization towards an anti-inflammatory phenotype through the STAT3/IL-10 axis, whereas CD146-negative extracellular vesicles did not have any effect. We next tracked the trafficking of labeled extracellular vesicles after intravenous injection in atherosclerotic ApoE-/- mice and visualized their incorporation into atheroma. After bi-weekly injections of extracellular vesicles for 6 weeks, only ApoE-/- mice treated with CD146 extracellular vesicles exhibited a significant reduction in atherosclerotic plaque, associated with an anti-inflammatory macrophage phenotype. We thus propose that treatment with CD146 extracellular vesicles could constitute a novel therapeutic option for reducing atherosclerosis.

ID: 42259955
Title: Aging in a highly polluted world: challenges and solutions to prevent Alzheimer's disease.
Abstract: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally and a leading cause of disability and death among the elderly. As populations age worldwide, the epidemiological burden of AD is expected to more than double by 2050, surpassing 150 million affected individuals. While genetic susceptibility, particularly the apolipoprotein E ε4 (APOE4) allele, modulates individual risk, most AD cases are late-onset and shaped by complex interactions between genetic background and modifiable environmental exposures. Environmental pollution has emerged as a critical and potentially preventable contributor to this burden. The 2024 Lancet Commission on Dementia Prevention, Intervention, and Care has identified 14 modifiable risk factors, with air pollution explicitly included. Drawing on evidence from human epidemiological cohorts, experimental animal models, and in vitro neuronal/glial systems, the present review aims to synthesize mechanistic evidence linking environmental pollutant classes to AD-relevant neuropathology. The review examines the growing body of evidence linking major categories of environmental pollutants (ambient particulate matter, heavy metals, pesticides, PFAS, and emerging contaminants including microplastics and nanoplastics) to AD risk and pathogenesis. Special attention is given to studies showing that the characteristic neuropathological features of AD may emerge in children and young adults chronically exposed to heavily polluted urban environments, which highlights critical concerns about when and how these changes develop throughout life. Shared mechanistic pathways through which environmental pollutants promote neurodegeneration are discussed, including neuroinflammation, oxidative stress, blood-brain barrier disruption, tau kinase dysregulation, epigenetic reprogramming, and gut-brain axis dysbiosis. The review also examines the amplifying role of biological aging on neurotoxic vulnerability and proposes a comprehensive, multi-level prevention framework addressing individual exposure reduction, clinical risk identification, and population-level policy interventions.

ID: 42265734
Title: Macrophage PSRC1 attenuates atherosclerosis via extracellular vesicle-mediated MBD2 delivery to induce PCSK9 promoter methylation in hepatocytes.
Abstract: Atherosclerotic cardiovascular disease (ASCVD) is driven by dysregulated lipid metabolism and chronic inflammation. However, the mechanisms governing immune-liver crosstalk in this context remain poorly defined. Proline/serine-rich coiled-coil protein 1 (PSRC1) is a known regulator of cholesterol metabolism, but whether macrophage-derived PSRC1 influences hepatic functions via intercellular communication is unknown. The relationship between macrophage PSRC1 and hepatic PCSK9 was examined in patients with coronary artery disease and murine models. We employed AAV6-mediated macrophage-specific targeting and whole-body Psrc1⁻/⁻ mice to evaluate cell-type-specific effects. Macrophage-hepatocyte communication was investigated using transwell systems and genetic blockade of EV secretion (sh-Rab27a). The selectivity of EV cargo loading was validated by protease protection assays and TSG101 interaction analysis. In vivo EV tracking (DiI-labeling) and ChIP-qPCR for DNMT recruitment were performed to elucidate the systemic and epigenetic mechanisms. Macrophage PSRC1 expression was significantly reduced in atherosclerotic conditions and inversely correlated with hepatic PCSK9 levels. Macrophage-specific PSRC1 depletion alone was sufficient to recapitulate the systemic hypercholesterolemia and accelerated atherosclerosis observed in whole-body knockout models. PSRC1 was found to interact with TSG101 to promote the selective loading of MBD2 into the EV lumen, a process confirmed by protease protection. These MBD2-enriched EVs were preferentially sequestered by the liver after systemic administration. Mechanistically, transferred MBD2 functioned as an epigenetic scaffold, recruiting DNA methyltransferases (DNMT1/3A) to the PCSK9 promoter to drive CpG hypermethylation and transcriptional repression. In vivo, administration of MBD2-enriched EVs significantly reduced hepatic PCSK9 protein, lowered plasma cholesterol, and enhanced plaque stability in ApoE⁻/⁻ mice. Our findings uncover a novel macrophage-liver epigenetic axis where macrophage PSRC1 controls systemic cholesterol homeostasis by regulating the EV-mediated delivery of MBD2. This "Reader-recruits-Writer" mechanism provides a refined understanding of immune-metabolic crosstalk and suggests that engineered EV-based MBD2 delivery represents a promising therapeutic strategy for ASCVD.

ID: 42268366
Title: Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer's Disease Pathogenesis.
Abstract: This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer's disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30-45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy-affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein-including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails-remain speculative and are presented as future research directions rather than established therapeutic interventions.

ID: 42278575
Title: Integration of Transcriptional Signatures from Brain Tissue and Plasma Extracellular Vesicles of a Preclinical Tauopathy Mouse Model.
Abstract: Tauopathies, including Alzheimer's disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls (n = 8/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing an association toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; n = 331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration suggest that pEV miRNA gene targets functionally mirrored genes involved in the brain's inflammatory and metabolic failure. We identified a preliminary candidate signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV), differentially enriched across both brain and periphery in PS19 compared to WT mice. These results suggest that the pEV non-coding landscape may partially reflect central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for potential peripheral indicators of central brain tau pathology.

ID: 42322185
Title: Evaluating emerging amyloid-β centric drugs for the treatment of Alzheimer's disease.
Abstract: The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress. The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy. Clinical benefits for Aβ-centric therapies are modest, ARIA poses ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD. Alzheimer’s disease (AD) is a growing global health problem, with no cure currently available. Most existing treatments only relieve symptoms and do not slow the underlying disease process. One of the earliest and most important biological changes in AD is the buildup of amyloid-β (Aβ), a protein that forms plaques in the brain. For this reason, many new drugs have been designed to remove Aβ or prevent it from accumulating. In recent years, several Aβ-targeting therapies have shown that they can successfully reduce amyloid plaques in the brain. These include monoclonal antibodies given by infusion or injection, vaccines that stimulate the immune system, and oral drugs designed to block the formation of toxic Aβ species. Some of these treatments have reached late-stage clinical trials, and a few have received regulatory approval in certain regions. However, while these drugs clearly reduce amyloid levels, their effects on memory and daily functioning are modest, especially when used after symptoms have already appeared. In addition, treatment can be associated with side effects such as brain swelling or small brain bleeds, requiring frequent medical monitoring, costly for healthcare systems. Most evidence so far comes from carefully controlled randomized clinical trials, and real-world experience remains limited. Current research is therefore shifting toward earlier treatment, including prevention in people at high risk, improved drug delivery methods, and combination approaches that also target other disease processes such as tau pathology, inflammation, and vascular or metabolic changes. New blood-based biomarkers are also making it easier to diagnose AD earlier and to select patients more precisely. Overall, Aβ–centered therapies represent an important scientific advance, but they are unlikely to be sufficient on their own. Future progress in AD treatment will depend on better understanding how amyloid may interact with other brain changes, identifying the right patients at the right time, and developing safer, more affordable, and more comprehensive therapeutic strategies.

ID: 42341994
Title: Morphine reprograms brain-derived extracellular vesicle cargo associated with synaptic remodeling in the prefrontal cortex.
Abstract: Extracellular vesicles (EVs) released by neurons and glia mediate intercellular communication and regulate synaptic and stress-related signaling in the brain. While chronic opioid exposure induces extensive neuroadaptations, the contribution of brain-derived EVs (BDEVs) remains poorly understood. Here, we isolated BDEVs from the prefrontal cortex of rats chronically exposed to morphine and performed integrated transcriptomic and proteomic profiling of EV cargo. Total RNA sequencing and unbiased proteomics identified morphine-associated changes enriched for pathways related to synaptic plasticity, endoplasmic reticulum stress, mitochondrial function, and neurodegeneration. Notably, the synaptic plasticity regulator Arc was increased at the mRNA level, and the ER stress marker Hspa5 was upregulated at both transcript and protein levels. Morphine-derived BDEVs induced transcriptional alterations in naïve cortical neurons, including changes in genes linked to synaptic remodeling and excitability. These findings suggest that BDEVs may contribute to opioid-induced neuroadaptations.

ID: 42352265
Title: Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer's Pathology in APP/PS1 Mice.
Abstract: Alzheimer's disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose-response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD.

ID: 42362005
Title: Apolipoprotein E in Alzheimer's disease: A review of APOE receptors, signalling pathways and therapeutic opportunities.
Abstract: Apolipoprotein E, a glycoprotein, is one of the strongest genetic risk factors for late-onset Alzheimer's disease. APOE is involved in the transport and metabolism of cholesterol, phospholipids and other lipids, synaptic function and neuroinflammation in the CNS. One of the key functions of APOE is to bind and deliver newly synthesized cholesterol and lipids to neurons through receptor-mediated endocytosis (LDLR, LRP1, VLDLR, APOER2). The APOE gene exists in three common isoforms: APOE2, APOE3, and APOE4, with distinct structural and functional properties. The three isoforms of APOE vary in their potential to bind and transport lipids and cholesterol, receptor affinity and clearance of Aβ. Among the three isoforms, APOE4 is one of the strongest risk factors for late-onset Alzheimer's disease, while APOE2 exerts a protective role highlighting the functional divergence among isoforms in CNS physiology. The functions of APOE are exerted through binding of APOE with members of the low-density lipoprotein receptor (LDLR) family, including LDLR, LRP1, VLDLR, and APOER2. So, approaches that potentiate the protective effects of APOE, like APOE mimetics, ABCA1 agonists, targeting APOE receptors like LDLR, LRP1, APOER2, and TREM2, might offer significant therapeutic benefits in Alzheimer's disease.

ID: 42423842
Title: Regulatory Effects of the PDE8B Inhibitor PF-04957325 on Cognitive Impairment and Neuroinflammation in Aβ-Induced Alzheimer's Disease Mouse Models.
Abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1-42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling. An AD model was induced by intracerebroventricular injection of Aβ1-42, followed by oral PF administration (0.1 mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro. PF significantly shortened escape latency (p < 0.01) and increased both platform crossings and target-quadrant dwell time (p < 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (p < 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (p < 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both p < 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation. PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.

ID: 42445022
Title: High-Throughput CETSA Identifies Small Molecule Modulators of ILT3 (LILRB4) with Functional Activity in Human iPSC-Derived Microglia for Alzheimer's Disease.
Abstract: Immune inhibitory signaling in microglia contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease (AD), yet small molecule modulators targeting these pathways remain largely unexplored. Here, we report the development of a high-throughput cellular thermal shift assay (HT-CETSA) platform for identification of small molecule binders targeting the inhibitory immune receptor ILT3 (LILRB4). Screening of ∼40 000 compounds yielded multiple validated hits, including IB15C, a submicromolar ILT3 binder identified through preliminary structure-activity relationship optimization. Orthogonal validation by microscale thermophoresis, surface plasmon resonance, docking, and site-directed mutagenesis confirmed direct and target-specific ILT3 engagement. Functionally, IB15C disrupted the ILT3-ApoE interaction and restored microglial activity in human iPSC-derived microglia, reducing SHP1/2 and NF-κB signaling, suppressing IL-1β secretion, and enhancing Aβ uptake. IB15C also demonstrated favorable in vitro pharmacokinetic and safety properties, supporting further development of ILT3-targeted neuroimmune therapeutics.

ID: 42449389
Title: Ferritin-ApoE nanocarrier for targeted therapy of neuromyelitis optica spectrum disorder in mice.
Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS), characterized by anti-aquaporin 4 (AQP4) antibody-mediated damage to astrocytes, resulting in subsequent demyelination. Our prior work identified the protective effects of the apolipoprotein E130-149 (ApoE130-149) peptide in NMOSD mice by promoting astrocyte-microglia intercellular communication. However, its therapeutic potential is restricted due to the limited penetration of the blood-brain barrier (BBB) with systemic administration. Here, we designed a heavy-chain ferritin (HFn)-based nanocarrier containing the ApoE130-149 peptide (HFn-ApoE130-149), specifically engineered for CNS delivery. HFn-ApoE130-149 was constructed through genetic engineering by fusing the coding sequence of HFn with that of the ApoE130-149 peptide in a recombinant plasmid. An acute NMOSD mouse model was induced by transcranial co-injection of AQP4-IgG and human complement (hC) into the brain. The distribution of Cy5.5-labeled HFn-ApoE130-149 post intravenous injection was tracked using in vivo fluorescence imaging to confirm its presence in the brain and peripheral organs. Lesions in the brain were quantified using T2-weighted 7 Tesla magnetic resonance imaging (7T-MRI). Neuropathological features of NMOSD were evaluated by immunostaining of brain sections. Neuroinflammation and immune cell infiltration were analyzed via flow cytometry. The key signaling pathways regulated by HFn-ApoE130-149 were investigated through Western blot (WB) analysis. The interaction between HFn-ApoE130-149 and its receptors was validated through co-immunoprecipitation and visualized on microglia using proximity ligation assay (PLA). Finally, the therapeutic effect on spatial learning and memory was evaluated using the Morris water maze (MWM) test. The HFn-ApoE130-149 effectively crossed the BBB, attenuated lesion progression and demyelination, as well as preserved AQP4 expression and astrocytic integrity in NMOSD mice. The treatment induced a spatial and phenotypic restructuring of the astrocytic response, notably reducing excessive astrocyte accumulation around lesions while encouraging a proliferative and reparative phenotype. Furthermore, HFn-ApoE130-149 influenced microglial polarization towards an anti-inflammatory state, reducing infiltration of peripheral immune cells. Mechanistically, HFn-ApoE130-149 exerted its anti-inflammatory effects through the low-density lipoprotein receptor-related protein 1 (LRP1) -nuclear factor kappa B (NF-κB) signaling axis in microglia. Functional binding of HFn-ApoE130-149 to LRP1 suppressed inhibitor of NF-κB (IκBα) phosphorylation, thereby inhibiting NF-κB nuclear translocation and the subsequent release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Knocking down LRP1 reversed these effects, highlighting the importance of the LRP1-NF-κB signaling axis in the nanotherapeutic's efficacy. Treatment with HFn-ApoE130-149 improved spatial learning and rescued memory deficits in NMOSD mice. This study demonstrates that the engineered nanodrug HFn-ApoE130-149 is a promising targeted therapy for alleviating NMOSD pathology by enhancing BBB penetration and suppressing neuroinflammation through the LRP1-NF-κB signaling axis.

ID: 42458512
Title: Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD. The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-κB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS. DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-κB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE. DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.

ID: 42461334
Title: Oral Microbial Extracellular Vesicles as Novel Mediators of Alzheimer's Pathogenesis: A Critical Review of the Periodontal-Brain Axis.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose origins extend beyond the brain. Chronic periodontitis has emerged as a modifiable risk factor, and extracellular vesicles (EVs) have recently been proposed as important mediators of the periodontal-brain axis. Periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) release bacterial EVs enriched with virulence factors including gingipains, lipopolysaccharide, and regulatory RNAs. These vesicles can enter systemic circulation, interact with the blood-brain barrier, activate microglia, and trigger inflammatory signaling pathways such as NF-κB and NLRP3. These processes contribute to neuroinflammation, amyloid-β accumulation, and tau hyperphosphorylation, hallmarks of AD pathology. Host-derived EVs further contribute to this complex signaling network by facilitating intercellular communication and potentially propagating pathogenic proteins while also carrying protective molecules. Preclinical studies suggest that periodontal-derived vesicles can reach the hippocampus and impair cognition, while clinical studies have detected P. gingivalis DNA and gingipains in AD brain tissues. EV-associated biomarkers in blood or cerebrospinal fluid and engineered therapeutic vesicles represent promising tools for early diagnosis and intervention. Targeting oral microbial EVs may therefore offer novel avenues for AD prevention and therapy.

ID: 42465741
Title: Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.
Abstract: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which amyloid-β accumulation, tau pathology, chronic neuroinflammation, cerebrovascular impairment, and synaptic dysfunction act as interconnected rather than independent processes. Physical exercise is protective against several of these features, but how its peripheral effects produce coordinated changes in the brain remains only partly defined. Soluble exerkines explain part of this benefit, but they act individually, do not protect labile cargo such as RNA, and carry little information about their cell of origin. Extracellular vesicles (EVs) offer a complementary mechanism. By packaging diverse cargo within a membrane, they co-deliver several signals at once, protect labile cargo in transit, and carry a profile that partly reflects the state and origin of the releasing cell. In this review, we develop a multi-organ signaling framework in which exercise-conditioned EVs link peripheral exercise adaptation to AD-related brain pathology. We examine how exercise reshapes EV biogenesis, the circulating EV pool, and EV engagement with the neurovascular interface. We then map how exercise-conditioned EVs intersect with amyloid aggregation and clearance, tau propagation, neuroinflammation, blood-brain barrier integrity, and synaptic and neurogenic resilience, and which tissues contribute to the exercise-responsive EV pool. Several bottlenecks keep the field at the level of association rather than causation, including cargo heterogeneity, uncertain tissue-of-origin attribution, and the gap between describing cargo and demonstrating its function. This framework outlines a realistic, staged route from current associative evidence toward clinical application, in which exercise-conditioned EVs serve first as biomarkers of exercise responsiveness and later as engineered therapeutic platforms for AD.

ID: 42469634
Title: Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models. The study utilized SOD1G93A mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-κB signaling pathway. In SOD1G93A mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-κB pathway. The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.

ID: 42469846
Title: Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.
Abstract: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system. Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD. LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming. Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.

ID: 42496844
Title: Targeting eHsp90α/GRP78 signaling-mediated endothelial barrier dysfunction in diabetic atherosclerosis: evidence from clinical and experimental studies.
Abstract: Early detection of diabetic atherosclerosis (DAS) remains challenging, and the mechanisms underlying endothelial barrier dysfunction in this condition are not fully understood. Extracellular Hsp90α (eHsp90α) and the ER stress marker GRP78 have been implicated in vascular injury; however, their roles in DAS remain unclear. Therefore, this study aimed to investigate the association of eHsp90α and GRP78 with DAS and explore the underlying mechanisms. We recruited patients with diabetes mellitus (DM) and patients with DAS. We then compared the levels and potential efficacies of serum eHsp90α and the ER stress marker GRP78 between the two groups. We subsequently conducted cytological experiments and experiments with ApoE-/- mice to further explore the underlying mechanisms involved. The serological analysis revealed that the levels of serum eHsp90α and the ER stress marker GRP78 were significantly higher in the DAS group than in the DM group and that the eHsp90α level was correlated with GRP78 level. The association and preliminary discriminative performance of the combination of eHsp90α and GRP78 levels were appeared higher than that of either marker alone. In addition, GRP78 plays a mediating role in the relationship between eHsp90α and DAS. Furthermore, the expression of GRP78 was higher in both diabetic ApoE-/- mice and DAS patients than in control ApoE-/- mice and AS patients. Cytological experiments revealed that eHsp90α induced endothelial barrier dysfunction mediated by ER stress via the LRP1 receptor. Our findings suggest that eHsp90α and GRP78 are associated with diabetic atherosclerosis and may be associated biomarkers with potential discriminative value, although further validation is required. The eHsp90α-LRP1-ER stress pathway may contribute to endothelial barrier dysfunction. However, further large-scale and longitudinal studies are required to validate these findings.

ID: 42496889
Title: Systems pharmacology and targeted transcriptional profiling suggest the putative neuroprotective role of Leuconostoc mesenteroides in an in vitro Alzheimer's disease model.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-beta (Aβ) accumulation, mitochondrial failure, and neuroinflammation. While probiotics show therapeutic potential via the gut brain axis, the molecular mechanisms remain poorly understood. This study investigated the neuroprotective potential of Leuconostoc mesenteroides lysate and its bioactive metabolites in an Aβ-induced SH-SY5Y neuroblastoma model. SH-SY5Y cells were challenged with Aβ and treated with L. mesenteroides lysate. Neuroprotective effects were evaluated via ROS accumulation, SOD1, APOE, NOS2, and mitochondrial dynamics (MFF, OPA1) using qPCR and WB. Potential mechanisms of action were explored computationally through integrated genome mining (antiSMASH 7.0), molecular docking (CB-Dock2), and systems pharmacology analysis (STRING/KEGG/R-studio) to identify candidate metabolites and host targets. L. mesenteroides lysate significantly attenuated Aβ-induced ROS levels and upregulated SOD1, enhancing antioxidant capacity. The lysate effectively downregulated APOE expression and restored mitochondrial homeostasis by reducing mitochondrial fission (MFF) and promoting fusion (OPA1). In silico analysis predected phytoene as a primary bioactive metabolite with significant theoretical binding affinity for APOE. Systems biology mapping revealed highly significant enrichment in PPAR signaling and cholesterol metabolism pathways (FDR < 10⁻⁵). Specifically, Cellular Component analysis highlighted robust interactions within protein-lipid complexes (FDR = 1.98e-16). L. mesenteroides lysate counteracts Aβ-induced neurotoxicity by modulating oxidative stress and restoring mitochondrial bioenergetics. Collectively, our findings suggest a theoretical Phytoene-PPAR-APOE signaling axis as a predictive framework for the observed cellular effects. We emphasize that phytoene represents a predicted candidate metabolite requiring future chemical characterization and biological validation.

ID: 42498931
Title: Mild Subcortical Stroke Induces Widespread Chronic Reactive Astrogliosis That Is Largely Unaffected by Microglia and Age.
Abstract: Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimer's disease. The cause of this pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke mostly confined to subcortical regions, similar to many silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, compared to the reactive microglia response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent reactive astrocytes. Aging mice exposed to MSCI exhibited a comparably strong response of reactive astrocytes and microglia as young mice. Lastly, reactive astrocytes persisted for at least nine months after MSCI. We propose that this mild ischemia model is valuable for examining the chronic effects of subcortical stroke. It may be especially useful for investigating the functional impact of reactive astrogliosis in regions distal from the primary injury site.

ID: 42500646
Title: Association between Alzheimer's disease and MHC-I antigen processing and presentation pathway: a narrative review.
Abstract: Alzheimer's disease (AD) is the most common cause of dementia worldwide and remains a major public health burden. Although amyloid-beta deposition and tau pathology are the defining pathological features of AD, increasing evidence indicates that immune dysregulation and chronic neuroinflammation also contribute to disease onset and progression. However, the specific immune pathways involved in AD and their mechanistic relevance remain incompletely understood. The major histocompatibility complex class I (MHC-I) antigen processing and presentation pathway has attracted growing attention because of its classical role in adaptive immunity and its potential functions within the central nervous system. In this narrative review, we summarize current evidence linking AD to the MHC-I, or human leukocyte antigen class I (HLA-I), pathway from genetic, molecular, cellular, and immunological perspectives. Available studies implicate the broader HLA region in AD susceptibility and suggest that alterations in HLA-I-related loci, antigen-processing machinery, MHC-I-associated molecules, and downstream immune responses may contribute to disease heterogeneity. At the molecular and cellular levels, changes in MHC-I molecules, antigen-processing machinery, and associated signaling pathways have been reported in microglia, neurons, astrocytes, and oligodendroglial lineage cells. In parallel, changes involving β2-microglobulin and the presence of expanded or cytotoxic like CD8+ T cells suggest that adaptive immune mechanisms may participate in AD pathology. Nevertheless, direct evidence demonstrating immune responses specific to particular antigens and restricted by HLA-I in human AD remains limited. Overall, current findings indicate that the MHC-I/HLA-I pathway may represent an important component of AD pathophysiology and contribute to disease progression by influencing immune homeostasis and cellular interactions within the central nervous system. Further studies integrating human tissue analysis, immunopeptidomics, spatial profiling, and paired T cell receptor approaches are needed to clarify its mechanistic, biomarker, and therapeutic significance.

ID: 42500791
Title: Association of sTREM2 and YKL-40 With Alzheimer's Disease Progression: A Systematic Review.
Abstract: Neuroinflammation is recognized as a core feature of Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and chitinase-3-like protein 1 (YKL-40) are fluid biomarkers of microglial and astrocytic reactivity associated with AD progression. However, their coupling to amyloid and tau pathology, stage-specific roles, and prognostic utility remain unclear. This systematic review synthesized evidence from 2021 to 2025 on associations of sTREM2 and YKL-40 with AD progression. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electrical and Electronics Engineers (IEEE) Xplore, and Web of Science were searched (Jan 2021-Dec 2025), with citation searching. Duplicates were removed using EndNote X21 (Clarivate, London, UK). Two independent reviewers screened records using the Population, Intervention, Comparison, Outcomes, and Study Design (PICOS) criteria, with disagreements resolved by a third reviewer. Original human studies measuring sTREM2 and/or YKL-40 across the AD spectrum were included. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). Due to heterogeneity in study design and outcomes, a narrative synthesis was performed. Thirteen studies were included: seven on sTREM2, five on YKL-40, and one on both. Six were low risk of bias, and seven were moderate. Cerebrospinal fluid (CSF) sTREM2 showed a biphasic pattern across disease stages, with early potential neuroprotective associations and later correlation with cortical atrophy and cognitive decline. A sex-APOE ε4 interaction was observed, with higher levels in female carriers. YKL-40 showed weak amyloid associations but strong coupling with tau pathology and neurodegeneration, influenced by vascular risk factors. Plasma YKL-40 predicted incident dementia and cognitive decline, and serum YKL-40 differentiated early dementia from controls with good diagnostic performance. sTREM2 and YKL-40 represent biologically distinct but complementary neuroinflammatory pathways in AD. sTREM2 reflects a stage-dependent microglial response, while YKL-40 reflects tau-associated astrocytic activation modulated by vascular factors. Longitudinal studies with concurrent biomarker assessment are needed to clarify their combined prognostic value.

ID: 42501172
Title: Glycerol-3-Phosphate Attenuates Hypoxic-Ischemic Brain Injury via Modulation of Microglia-Mediated Neuroinflammation.
Abstract: Hypoxic-ischemic encephalopathy (HIE) is a severe perinatal brain injury that often leads to neurological impairments in survivors. Currently, effective therapeutic strategies for HIE remain limited and require further exploration. Emerging evidence indicates that microglia-mediated neuroinflammation plays a pivotal role in the pathophysiology of HIE. Nevertheless, clinically effective anti-inflammatory agents specifically targeting HIE are still lacking. Glycerol-3-phosphate (G3P) is a biologically significant metabolite involved in various cellular metabolic pathways. In this study, we investigated the neuroprotective effects of G3P against hypoxic-ischemic (HI)-induced brain injury by modulating microglial activation. In LPS-treated microglia, G3P suppressed the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential (MMP), and promoted a shift toward an anti-inflammatory microglial phenotype. In addition, G3P treatment in zebrafish showed no toxicity and significantly mitigated HI-induced oxidative stress, while suppressing both the recruitment and pro-inflammatory activation of mpeg1⁺ macrophages and lyzc⁺ neutrophils. Moreover, administration of G3P dramatically reduced infarct volume and alleviated neuronal loss in rats with hypoxic-ischemic brain damage (HIBD). Y-maze and Morris water maze tests demonstrated that G3P treatment significantly enhanced spatial learning and memory in HIBD rats. Furthermore, G3P markedly reduced the hyperactivation of microglia and astrocytes in both cortical and hippocampal regions. Mechanistically, Immunofluorescence and Western blot analyses revealed that G3P exerted anti-inflammatory effects by inhibiting cyclic GMP-AMP synthase -stimulator of interferon genes (cGAS-STING) signalling pathway and its downstream TBK1/the nuclear factor kappa B (NF-κB) signaling pathway. These findings highlight G3P as a promising therapeutic candidate for HIE.

ID: 42501950
Title: Targeting the NLRP3 inflammasome in Alzheimer's disease: Mechanistic insights and therapeutic advances.
Abstract: Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K+ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.

ID: 42505375
Title: Stimulus-Based ApoE Alzheimer's Disease Induction Model Using Microglia-Containing Brain Organoids for Drug Discovery.
Abstract: Alzheimer's Disease (AD) is a multifaceted progressive neurodegenerative disease characterized by memory deficits and cognitive impairment. The disease is clinically diagnosed by the presence of β-amyloid (Aβ), hyperphosphorylated tau, and neurodegeneration. Animal models serve as an indispensable tool to understanding AD pathogenesis and evaluating potential therapeutic approaches. However, despite the development of more than 200 rodent models, species-specific differences limit the translational relevance. Brain organoids generated from induced pluripotent stem cells (iPSCs) have the potential to bridge the gap between transgenic mouse models and clinical trials in human patients. Herein, we describe a robust stimulus-based neuroimmune organoid model that demonstrates neuroinflammation, neurodegeneration, and lipid dysregulation with AD-relevant pathological markers. Using planar organoids containing neurons, astrocytes, microglia, and vascular cells, we performed in-depth characterization of the induced AD-like phenotype using supernatant proteomic analysis, immunofluorescence staining, NfL and GFAP release, scRNAseq, bulk RNAseq, and pathway analysis both acutely (24 h) and chronically (7 days). Furthermore, we show that the induced neuroinflammation, lipid dysregulation, and neurodegeneration can be ameliorated using small molecules. This defined inducible model system presents an opportunity for drug discovery and development using a complex multicellular brain microenvironment derived from human iPSCs.

ID: 42505400
Title: Microglia in Alzheimer's Disease: From Homeostatic Guardians to Multifaceted Drivers of Neuropathology.
Abstract: Background: Alzheimer's disease (AD) affects >55 million people worldwide and lacks disease-modifying therapies. Microglia, the CNS resident immune cells, dynamically transition between protective and pathological states during AD progression. Recent advances in single-cell sequencing and metabolomics reveal that microglial roles extend beyond simple M1/M2 polarization. This review synthesizes these advances into a framework integrating microglial plasticity, metabolic reprogramming, and intercellular communication in AD. Methods: We reviewed recent (2020-2026) studies on microglial biology in AD, focusing on DAM (disease-associated microglia) ontogeny, metabolic reprogramming, immune checkpoints, and glial crosstalk. Results: Microglia exhibit spatiotemporal heterogeneity, shifting from protective phagocytic phenotypes (M2, DAM1/2) in early AD to pro-inflammatory and exhausted states (M1, terminal inflammatory microglia [TIM], lipid droplet-accumulating microglia [LDAM]) as pathology advances. Key pathways-TREM2/SYK phagocytosis, Piezo1 mechanotransduction, TAM (Tyro3, Axl, Mer) receptor signaling, and metabolic regulators (HK2, iron, APOE4-driven lipid metabolism)-orchestrate these transitions. Microglia also interact with astrocytes, T cells, and peripheral immune cells via IL-3, complement C3, MHC-I and MHC-II, forming glial-immune networks that modulate Aβ clearance, tau propagation, and synaptic integrity. Conclusions: Precisely targeting microglial functional states, rather than broad immunosuppression, is a promising disease-modifying strategy for AD. Future therapies should integrate metabolic reprogramming, glial network regulation, and immune checkpoint modulation to preserve protective microglial phenotypes in early AD while suppressing pathological activation and exhaustion in advanced disease.

ID: 42510655
Title: From Inflammatory RNAs to Therapeutic Silencing: Deciphering the RNA-Inflammation Axis in Cancer and Neurodegeneration.
Abstract: Inflammation is a critical protective response that maintains tissue homeostasis. However, persistent or dysregulated inflammation contributes significantly to the progression of cancer and neurodegenerative diseases. Recent advances in RNA biology have identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as key modulators of inflammatory signaling networks. These RNA molecules regulate key pathways such as NF-κB, STAT3, MAPK, and PI3K/AKT, thereby influencing immune responses, tumor progression, neuronal survival, and cellular stress adaptation. In parallel, RNA-sensing receptors, including Toll-like receptors and RIG-I-like receptors, connect innate immune activation with chronic inflammatory pathology. Emerging evidence further demonstrates that inflammatory RNAs participate in epigenetic regulation, intercellular communication, and inter-organ crosstalk through extracellular vesicles and exosomes. In cancer, RNA-mediated feedback loops sustain tumor-promoting inflammation, metastasis, and immune evasion, whereas in neurodegenerative disorders, they contribute to glial activation, neuronal dysfunction, and progressive neuroinflammation. This review examines the mechanistic relationship between RNA dysregulation and inflammation across cancer and neurodegeneration, with particular emphasis on RNA signaling networks, exosomal communication, and targeted RNA-based therapeutics. Collectively, advances in understanding the RNA-inflammation axis may reveal new opportunities for precision diagnostics and next generation therapeutic interventions.

ID: 42516873
Title: Emerging biomarkers for Parkinson's disease in biological fluids.
Abstract: Early and accurate diagnosis of Parkinson's disease (PD) remains a challenge, hindering the efficient recruitment of patients into clinical trials aimed at disease modification. This underscores the urgent need for validated and clinically applicable biomarkers. Research continues to expand our knowledge of fluid biomarkers for detecting and monitoring PD progression. Cerebrospinal fluid α-synuclein (α-syn) seed amplification assays (SAA) have emerged as highly sensitive and specific biomarkers for the diagnosis of PD. The development of less invasive procedures using biological fluids such as serum or saliva would be more practical for routine clinical use. Recent data demonstrate the presence of pathogenic α-synuclein in the serum of PD patients compared with healthy controls, detected using real-time quaking-induced conversion (RT-QuIC) assays. Elevated ratios of pS129-α-syn and/or oligomeric α-syn to total α-syn have also been reported in PD. Future research should clarify differences in protein aggregate formation across various synucleinopathies. Promising advances toward a clinically useful blood-based diagnostic test for PD include the quantification of proteins released from neural-derived extracellular vesicles (NDEVs), such as oligomeric and phosphorylated α-syn, tau, and disease-associated microRNAs. Given the role of neuroinflammation in PD pathogenesis, inflammatory biomarkers, including interleukin (IL)-6, IL-10, tumor necrosis factor-α(TNF-α), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1), are under active investigation. Furthermore, fluid biomarkers associated with Alzheimer's disease pathology are being explored for their potential to predict motor and cognitive decline in PD and related synucleinopathies. Salivary EVs hold promise as a non-invasive source of PD biomarkers; however, robust validation in large, well-characterized cohorts is essential to improve the diagnostic and prognostic accuracy of PD.

ID: 42518751
Title: Neuroinflammation in Alzheimer's disease-associated sensory dysfunction: mechanistic links, actionable targets and therapeutic strategies.
Abstract: Alzheimer's disease (AD) is the most common cause of dementia and major public-health challenge in aging societies worldwide. Accumulating evidence suggests that olfactory and visual deficits can precede overt cognitive symptoms and are closely associated with amyloid-β deposition, pathological tau phosphorylation, and disease progression. Early sensory abnormalities in AD likely arise from converging pathological processes. Among these, chronic neuroinflammation marked by microglial and astrocytic reactivity, inflammasome activation and increased pro-inflammatory mediators might play a pivotal role linking sensory-circuit injury to neurodegeneration. A coherent synthesis of the inflammatory mechanisms underlying early olfactory and visual impairment in AD remains limited, and putative molecular pathways and interventions have not been fully integrated. We aimed to identify AD-related olfactory and visual or retinal abnormalities, combine core inflammatory pathways and their interactions with amyloid-β and tau pathology, and summarize actionable targets and candidate interventions along a "receptor-intracellular signaling-inflammasome-effector" axis, to inform earlier-stage detection and mechanism-guided intervention in AD.

ID: 42521030
Title: Is amyloid beta peptide a driver of inflammaging?
Abstract: Inflammaging, the chronic subclinical systemic inflammation accompanying aging, represents a critical pathogenetic mechanism underlying age-related neurodegenerative diseases. While amyloid beta (Aβ) peptides are established contributors to neuroinflammation in Alzheimer's disease, their role in aging-related subclinical inflammation remains insufficiently elucidated. In humans, Aβ exhibits dual functions: it supports neuronal activity, survival, and protection against neurotrauma, while also promoting inflammation and central nervous system dysfunction. This review highlights the beneficial effects of Aβ, including its antioxidant and antipathogenic properties, and synthesizes current knowledge of the molecular mechanisms driving Aβ-associated inflammaging. We structure this analysis across distinct brain cell types - microglia, astrocytes, oligodendrocytes, neurons, pericytes, and endothelial cells - and consider additional factors influencing Aβ-related neuroinflammation. Finally, we examine strategies to counteract the detrimental effects of Aβ, focusing on Aβ physiological clearance via the blood-brain barrier and glymphatic system, as well as therapeutic interventions. Understanding Aβ-driven inflammaging mechanisms offers new therapeutic avenues for early intervention in age-related neurodegenerative diseases, particularly in genetically susceptible populations. Targeting Aβ-associated inflammaging reframes Aβ not solely as a pathological marker but also as a context-dependent contributor to inflammatory processes during brain aging.

ID: 42525165
Title: From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.
Abstract: The brain contains a large proportion of the body's cholesterol, highlighting its importance in central nervous system function. Cholesterol supports neuronal membrane structure, synapse formation, synaptic vesicle activity, receptor signaling, and myelin integrity. Because the blood-brain barrier limits the entry of peripheral lipoproteins, the brain relies mainly on local cholesterol synthesis, transport, recycling, and turnover. This review examines the mechanisms that regulate astrocyte-to-neuron cholesterol transfer and explains how defects in SREBP-dependent synthesis, ApoE lipidation, ABC transporter-mediated export, neuronal uptake, intracellular trafficking, and cholesterol turnover contribute to synaptic dysfunction and neurodegeneration. In the adult brain, astrocytes are an important source of cholesterol for neurons. Astrocytic cholesterol synthesis is regulated by sterol regulatory element-binding proteins, which control the expression of key cholesterol-biosynthetic genes. Astrocytes release cholesterol in ApoE-containing lipoprotein particles through ATP-binding cassette transporters. Neurons acquire astrocyte-derived cholesterol through LDLR/LRP1, redistribute it via NPC1/NPC2, and eliminate excess cholesterol as 24 S-hydroxycholesterol through CYP46A1. Disruption of this pathway impairs membrane organization, lipid raft signaling, synaptic function, and neuronal survival. These disturbances are associated with Alzheimer's disease, Huntington's disease, and multiple sclerosis.

ID: 42528139
Title: Lineage-tailored vesicles from human retinal ganglion-like cells drive metabolic homeostasis and bioenergetic recovery in glaucoma.
Abstract: Retinal ganglion cells (RGCs) exhibit high bioenergetic demands, rendering them vulnerable to mitochondrial dysfunction and metabolic collapse during glaucomatous neurodegeneration. Therapeutic strategies capable of restoring mitochondrial homeostasis in human RGCs remain limited. We established a human retinal ganglion-like cell (RGLC) model of mitochondrial injury and evaluated neuroprotective efficacy of small extracellular vesicles (sEVs) derived from either undifferentiated BRN3B-H9 cells or differentiated lineage-tailored RGLCs. RGLC-derived sEVs (RGLC-sEVs) conferred robust neuroprotection, significantly enhancing neuronal survival, preserving neurite architecture, and mitigating mitochondrial stress following injury. These effects were reproducible in mixed retinal cultures and in an ocular hypertension mouse model of glaucoma, with neuroprotective benefits observed throughout the retinal landscape. Mechanistically, untargeted metabolomic profiling revealed extensive metabolic reprogramming involving oxidative phosphorylation, amino acid utilization, lipid metabolism, and redox regulatory pathways. In vitro tracking studies confirmed efficient uptake of sEVs by injured RGLCs, confirming effective vesicular cargo delivery under conditions that promote neuroprotection and metabolic recovery. Functional bioenergetic analysis further validated restoration of mitochondrial-glycolytic coupling and improved cellular energetic resilience. Collectively, our findings establish lineage-tailored RGLC-sEVs as a potent, cell-specific therapeutic candidate capable of reprogramming metabolic networks and restoring bioenergetic homeostasis in glaucomatous neurodegeneration, highlighting their translational potential for neuroprotective intervention in optic neuropathies.

ID: 42541636
Title: The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.
Abstract: Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.

ID: 42543397
Title: Autonomous intranasal delivery systems for central nervous system therapeutics.
Abstract: Intranasal delivery provides a rapid, non-invasive route to the central nervous system, bypassing the blood-brain barrier and first-pass metabolism. However, its therapeutic potential remains constrained by the nasal cavity's complex anatomy, the restricted surface area and permeability of the olfactory epithelium, and short drug residence times. Recent advances in nanotechnology and synthetic biology have enabled the development of autonomous and programmable delivery systems that can target the olfactory epithelium, enhance brain entry and sustain therapeutic release. This review highlights current strategies for engineering intranasal drug delivery vectors that can replicate or extend cellular functions to enable autonomous nose-to-brain drug delivery. These vectors include: synthetic nanoparticles that mimic essential cellular activities and allow for modular surface modification; extracellular vesicles that naturally carry therapeutic cargo and exhibit parent-cell-derived tropism; and living therapeutics, such as engineered microbes, viruses or stem cells, that respond dynamically to host environments and can be genetically programmed for precise payload production. Emphasis is placed on the modular design of functional components, host-responsive interactions tailored to anatomical and physiological cues, and the integration of programmable functions that collectively drive delivery autonomy and therapeutic efficacy. Together, these advances position intranasal delivery as a versatile platform for treating neurological disorders, offering a foundation for future translational development.

ID: 42545206
Title: Neutrophils Promote Metabolic Dysfunction-Associated Steatotic Liver Disease Through Extracellular Vesicle-mediated Lipid Transfer.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis are leading causes of chronic liver disease, yet the contribution of neutrophils to early hepatocellular lipid accumulation remains poorly understood. Here, we investigated the role of neutrophils in hepatic lipid deposition during early MASLD development. Neutrophils acquired extracellular fatty acids (FAs) via FATP2 and CD36 and stored them as triglycerides (TGs). These lipid-laden neutrophils (LNs) did not utilize FAs for energy production or lipid mediator synthesis but instead transferred lipid cargo to hepatocytes through extracellular vesicles (EVs). Neutrophil-derived EVs were enriched with TGs and lipid metabolism-regulating microRNAs, augmenting TG accumulation in hepatocytes. Peripheral neutrophils isolated from high-fat diet-fed mice exhibited a lipid-laden phenotype, and adoptive transfer of LNs and EVs derived from LNs increased hepatic fat accumulation in recipient mice. In patients with MASLD, circulating neutrophils showed lipid droplet accumulation with increased TGs and enrichment of lipid-associated miRNAs while plasma EVs were also enriched with TGs and lipid-associated miRNAs. Single-cell RNA sequencing of peripheral immune cells identified a neutrophil subpopulation characterized by enhanced lipid-handling and EV-related gene expression. These findings identify neutrophil-mediated lipid transfer via EVs as a mechanistic link between innate immune activation and hepatic lipid accumulation during early MASLD.

ID: 42549510
Title: Intranasal Administration of Isoeugenol Improves Memory Deficits in APP/PS1 Old Mice-A Role Beyond Nrf2 Activation?
Abstract: Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease-modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol-rich Keap1, and many are Michael acceptors, such as low-molecular-weight (LMW) skin allergens. However, LMW allergens-induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD-specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10-month-old AD double-transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2-dependent anti-inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.

ID: 42549659
Title: Lower cardiac output is a risk factor for faster cerebral atrophy over a 11-year follow-up period in APOE-ε4 carriers.
Abstract: Subclinical lower cardiac output (volume of blood pumped per minute) cross-sectionally relates to smaller cerebral gray matter volumes in older adults. This study relates cardiac output to longitudinal gray matter volumes among middle-aged and older adults over an 11-year period. Linear regression (cross-sectional) and mixed effects (longitudinal) models related baseline cardiac output to gray matter volume trajectory, adjusting for demographic factors. Secondary models tested cardiac output × apolipoprotein E (APOE) -ε4 status interactions. Lower cardiac output related to smaller brain volumes (p-values < 0.04) in APOE-ε4 positive participants only. In longitudinal models, baseline cardiac output interacted with APOE-ε4 status (p = 0.006). Lower baseline cardiac output related to greater increase in inferior lateral ventricle volume over time in APOE-ε4 carriers (p = 0.01) only. Results suggest among APOE-ε4 carriers, subclinical cardiac dysfunction relates to greater neurodegeneration cross-sectionally and longitudinally. However, results must be interpreted with caution and replicated.

ID: 42552042
Title: Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.
Abstract: Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.

ID: 42552753
Title: The role of polygenic risk in Alzheimer's disease prediction for African Americans.
Abstract: African Americans (AAs) face a higher risk of Alzheimer's disease and related dementias (ADRD) than European Americans (EUs), yet the utility of polygenic risk scores (PRS) in AAs remains underexplored. A standardized dementia PRS was evaluated in the Chicago Health and Aging Project (n = 4336; 61% AA) for associations with ADRD and cognitive trajectories over 8.4 years. PRS predicted ADRD more strongly in EUs (c-index 0.86) than AAs (0.77); however, it conferred higher risk in AAs (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.04-1.78) compared to EU (HR = 1.13, 95% CI: 0.88-1.44). The PRS remained predictive among AAs after apolipoprotein E (APOE) ε4 adjustment (HR = 1.53, 95% CI: 1.03-2.27). Higher PRS associated with lower baseline cognition and faster decline (p < 0.05). PRS conferred greater ADRD risk in AAs and comparable rates of cognitive decline, despite stronger discrimination in EUs, adding to the limited knowledge of genetic contributions to ADRD risk among AAs beyond APOE ε4 alleles.

ID: 42556435
Title: Extracellular vesicle-mediated immune regulation in central nervous system diseases: Mechanistic insights and exercise interventions.
Abstract: Central nervous system (CNS) diseases are major contributors to long-term disability and cognitive impairment, with neuroinflammation and immune dysregulation closely implicated in their pathogenesis. Extracellular vesicles (EVs) are phospholipid bilayer-enclosed membrane vesicles secreted by diverse cell types that mediate communication between the periphery and CNS through the delivery of various bioactive molecules, including proteins, lipids, and non-coding RNA, thereby exerting immunomodulatory functions. Accumulating evidence has demonstrated that EVs contribute to immune regulation during the initiation and progression of CNS diseases by modulating pathological processes, including neuroinflammation, pro-inflammatory polarization of glial cells, NLRP3 inflammasome activation, and pyroptosis. Previous studies have reported that exercise exerts neuroprotective effects in CNS diseases through EVs-mediated immune regulation. This review summarizes and critically evaluates the biological characteristics of EVs, EV-mediated immunoregulatory mechanisms, the roles of EV-mediated immunoregulation in CNS diseases, and exercise interventions, thereby providing theoretical insights into the beneficial effects of exercise on brain health.

ID: 42556482
Title: A role for apolipoprotein E4 (ApoE4) in the pathogenesis of depressive symptoms and Alzheimer's disease.
Abstract: Depression is a chronic mental disorder that is often difficult to diagnose and mostly left untreated. Apolipoprotein E (ApoE) is a lipid transport protein that plays a central role in the metabolism of plasma lipoproteins and the transport of lipids within tissues. Among its three major isoforms, only ApoE4 has a unique structural variant that confers significant neurotoxicity not present in the other two subtypes. ApoE4 not only disrupts lipid metabolism but also interferes with neuroimmune regulation and mitochondrial dynamics, thereby impairing synaptic integrity. It is a major genetic risk factor for Alzheimer's disease (AD) and accelerates its age of onset. Although developing depression in midlife may be a risk factor for AD, the underlying mechanisms by which ApoE4 influences depression or depression-related behaviors associated with AD remain fragmented, and systematic integrative reviews on this topic are scarce. We integrate existing evidence to elucidate the role of ApoE4 in depression or AD-associated prodromal depressive-like behaviors, with a focus on how its dysfunction disrupts cellular lipid homeostasis, impairs synaptic plasticity, and damages mitochondrial function. We also explored specific therapeutic strategies targeting the pathological defects of ApoE4 that enhance synaptic resilience, and utilizing conformational modulating small molecules such as EZ-482 and ALZ-801 to treat depressive symptoms in early AD. Thus, these findings indicate that ApoE4 may influence the progression of depressive phenotypes through multiple pathological pathways, making it a promising therapeutic target for treating depression comorbid with early AD.

ID: 42556769
Title: Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
Abstract: Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model. BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis. Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo. Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.

ID: 42557952
Title: In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.
Abstract: Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.

ID: 42561582
Title: Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study.
Abstract: About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies. Our objective was to extend SOMI's findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's(A4) study. Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up. Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE ε4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15-1.92 p=.003) for SOMI-1, to 1.83 (1.32-2.54, p ≤ 0.001) for SOMI-2, and to 3.04 (1.97-4.68, p ≤ 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model. SOMI's risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.

ID: 42564156
Title: APOE ε4, physical activity, and the brain: a review of systematic reviews.
Abstract: Physical activity (PA) is often proposed as a modifiable strategy to reduce cognitive decline and dementia risk, particularly among individuals at elevated genetic risk for Alzheimer's disease (AD). However, it remains unclear whether the existing literature tests PA at the disease stage and in the populations most likely to show benefit. This umbrella review evaluated whether associations between PA and cognitive, fluid biomarker, neuroimaging, and vascular/metabolic outcomes differ by apolipoprotein E ε4 (APOE ε4) genotype across stages of cognitive aging, with particular attention to how study design and baseline cognitive status shape interpretation of the evidence. Systematic reviews and meta-analyses were screened for primary studies examining PA in adults classified by baseline cognitive status as cognitively unimpaired, mild cognitive impairment (MCI), or dementia. Primary studies reporting APOE ε4-stratified outcomes were extracted and qualitatively synthesized by outcome domain, cognitive stage, and study design. Of 2,100 records identified, seven systematic reviews met inclusion criteria, yielding 68 unique primary studies. Favorable associations between PA and cognitive, biomarker, neuroimaging, and vascular/metabolic outcomes were most often reported in observational studies of younger or cognitively unimpaired adults. Several studies suggested stronger associations among APOE ε4 carriers, including midlife cognitive associations, neuroimaging markers, and vascular/metabolic outcomes such as lipid profiles. In contrast, randomized controlled trials were few, generally enrolled older adults with MCI or dementia, included small APOE ε4 subgroups, and reported largely null or mixed genotype-specific effects. The current evidence does not establish a definitive APOE ε4-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk APOE ε4 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.

ID: 42565245
Title: A randomized phase 1b/2 trial of ABBV-916 in adults with early Alzheimer's disease.
Abstract: ABBV-916, an anti-amyloid immunotherapy, was evaluated in patients with early Alzheimer's disease (AD). This phase 1b/2, double-blind, placebo-controlled study consisted of two stages: multiple ascending dose (Stage A) and dose expansion (Stage B). In Stage A, patients were randomized to one of six planned cohorts to receive intravenous ABBV-916 (10 mg to 3000 mg) or placebo monthly through week 24. Assessments included amyloid PET, blood-based biomarkers, pharmacokinetics (PK), and safety. Dose selection for Stage B was to be based on results from Stage A. One hundred six patients were randomized to ABBV-916 or placebo. The 3000 mg dose was reduced to 2000 mg and subsequently to 900 mg after safety review. Dose-proportional PK were observed, and amyloid reduction was observed over 24 weeks at doses ≥300 mg. Most adverse events were non-serious amyloid-related imaging abnormalities. The program ended before dose expansion due to business considerations. Amyloid clearance rate and safety of ABBV-916 were generally comparable to approved anti-amyloid AD therapies. NCT05291234.

ID: 42569203
Title: APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.
Abstract: Gene-environment interplay contributes to the heterogeneous etiology of Alzheimer's disease (AD). Hypertension (HTN) is a major modifiable vascular risk factor, but whether its association with AD differs across APOE genotypes remains unclear. We examined the interaction between HTN and APOE genotypes in relation to incident AD and explored plasma proteomic correlates as potential biological clues. Longitudinal data from 318,923 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up period of 13 years. Cox proportional hazards models with competing-risk adjustment for death were used to assess additive and multiplicative interactions between HTN and APOE genotypes. Plasma proteomic data from 34,141 participants, covering 2790 proteins, were further analyzed using mediation and bioinformatics approaches. HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 carriers and ε4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function. The association between HTN and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. These findings suggest genotype-dependent heterogeneity in vascular contributions to AD risk. Proteomic results should be interpreted as exploratory biological clues and require further validation. The association between hypertension and incident Alzheimer’s disease differed across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. Multiplicative, but not additive, interaction supports cautious interpretation of clinical implications and does not establish absolute risk scale synergy. Exploratory plasma proteomic analyses identified PSAP-, GM2A-, and BRK1-related signals involving sphingolipid, lysosomal, and WAVE-complex biology.

ID: 42570239
Title: APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.
Abstract: Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.

ID: 42570705
Title: Metabolic reprogramming-driven neuroimmunoregulation: Key mechanisms and therapeutic opportunities and challenges in central nervous system disorders.
Abstract: Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.

ID: 42575454
Title: Differential consequences of traumatic brain injury in the hippocampal hemispheres of male rats and the beneficial effect of neuropeptide Y.
Abstract: Traumatic brain injury (TBI) initiates a complex cascade of secondary injury mechanisms, including neurovascular dysfunction, neuroinflammation, and glial activation, which progressively contribute to long-term neurological deficits. Although the primary mechanical insult is typically unilateral, secondary pathological processes can extend beyond the impact site. However, the spatiotemporal evolution of these bilateral alterations remains poorly understood. Neuropeptide Y (NPY) is an endogenous neuromodulator with anti-inflammatory and neuroprotective properties, making it a promising candidate for limiting secondary brain injury. Here, we characterized the bilateral hippocampal response to experimental TBI and evaluated whether early intranasal NPY administration post-TBI attenuates neurovascular and neuroinflammatory alterations while improving behavioral outcomes. Male Sprague-Dawley rats were subjected to a closed-head weight-drop model of TBI and treated intranasally with NPY (100 μg/animal) or vehicle 30 min after injury. Molecular, histological, and behavioral analyses were performed 48 h and 7 days post-injury. We concluded that TBI induced distinct spatiotemporal pathological responses in the hippocampi. The ipsilateral hippocampus exhibited early blood-brain barrier (BBB) disruption and astrocytic alterations, whereas the contralateral hippocampus developed a more pronounced and sustained inflammatory response characterized by microglial activation and increased expression of inflammatory and endothelial activation markers. Early intranasal NPY administration attenuated these bilateral pathological alterations by preserving BBB integrity, reducing neuroinflammatory responses, and normalizing glial morphology. These neurobiological effects were accompanied by improvements in spatial working memory and anxiety-related behaviors. Collectively, our findings demonstrate that unilateral TBI induces distinct bilateral secondary injury responses within the hippocampus and identify early intranasal NPY administration as a promising strategy. Further investigation is warranted to clarify the underlying mechanisms and establish the long-term therapeutic potential of NPY.

ID: 42576814
Title: Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.
Abstract: Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews. Exosomes are tiny natural particles released by cells that act as messengers, carrying proteins and genetic material between cells. Scientists are increasingly studying these particles because they may help deliver medicines to the brain and spinal cord, where many treatments struggle to reach due to protective barriers. This review explains how exosomes are formed, how they can be modified to carry drugs or therapeutic molecules, and how they may help treat diseases affecting the nervous system, including Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, spinal cord injury, and certain neuropsychiatric disorders.We also discuss the advantages of exosomes compared with conventional drug delivery systems and summarize recent advances in engineering strategies that improve their targeting abilities. Although laboratory studies have produced encouraging results, many challenges remain before exosome-based therapies can become routine treatments. These include difficulties related to large-scale production, quality control, safety, and ensuring that exosomes reach the desired tissues without causing unwanted effects.In addition, this review highlights current clinical studies and discusses the steps needed to translate these discoveries into real-world therapies. Overall, exosomes represent an exciting and rapidly evolving area of research that may contribute to the development of safer and more effective treatments for neurological disorders in the future.

ID: 42580438
Title: Current Clinical Evidence on Nose-to-Brain Drug Delivery.
Abstract: Intranasal delivery is increasingly recognised as a promising strategy for direct drug transport to the brain via the nose-to-brain pathway, bypassing the blood-brain barrier and improving therapeutic efficacy. This approach has shown potential in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and acute psychiatric conditions, as well as in emergencies such as anxiety attacks and migraine episodes. Recent clinical studies investigating intranasal formulations of rivastigmine, insulin, and olanzapine, among other drugs, have provided encouraging evidence supporting the clinical translation of this delivery strategy. In addition, FDA-approved intranasal products indicated for central nervous system disorders, including diazepam and midazolam for seizure management, and triptans for migraine, demonstrate the growing clinical relevance of intranasal drug delivery. Both preclinical and clinical studies have reported encouraging outcomes, particularly when intranasal delivery is combined with nanoformulations and specialised delivery devices designed to enhance olfactory deposition. Intranasal administration is non-invasive, painless, and may improve patient adherence while enhancing brain bioavailability. Nevertheless, further well-designed clinical studies are required to establish the long-term safety, efficacy, and clinical applicability of this delivery strategy.

ID: 42585285
Title: Correlation analysis between complement proteins and Alzheimer's disease.
Abstract: BackgroundThe prominent pathological features of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau pathology. The complement cascade is closely related to AD-associated pathological processes; however, the precise mechanisms underlying its contributions remain incompletely elucidated.ObjectiveWe aim to investigate the changes in complement protein expression during AD progression.MethodsThis study enrolled 285 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants were classified into biomarker-defined groups based on predefined cutoff values for Aβ42 and phosphorylated tau (P-tau). We compared cerebrospinal fluid (CSF) levels of complement proteins (C1q, C2, C3, C4a, C5, C6, C8b, and factor B) across these subgroups. Furthermore, we explored their associations with core AD biomarkers (Aβ42, P-tau, and T-tau) and clinical characteristics. Additionally, we investigated age-related changes in complement gene expression within the cerebral cortex of 3xTg mice using single-nucleus RNA sequencing.ResultsComplement protein levels in the CSF of A + subjects were significantly lower than those in A- subjects, and complement protein levels were positively correlated with Aβ pathology. Complement protein levels were influenced by factors such as age, gender, body mass index, APOE genotype, and hypertension. Compared with control mice, the complement gene C1qa in microglia was upregulated throughout the entire pathological cycle in 3xTg AD mice.ConclusionsComplement proteins undergo significant changes during the pathogenesis of AD, and alterations in their levels may reflect early pathological changes in AD and warrant further investigation. Notably, our findings suggest that microglia may contribute to complement-mediated pathological processes associated with AD.

ID: 42585680
Title: Zexieyin formula ameliorates high-fat diet-induced cognitive impairment via pericyte-associated LRP1 modulating CypA/NF-κB/MMP-9 pathway.
Abstract: The global rise in obesity and metabolic syndrome is increasingly recognized as a major risk factor for cognitive decline and neurodegenerative diseases. Chronic high-fat diet (HFD) consumption disrupts blood-brain barrier (BBB) integrity, a pivotal pathological event that facilitates neurotoxic infiltration, neuroinflammation, and neuronal injury. Brain pericytes play a central role in maintaining BBB function and are particularly vulnerable to HFD-induced metabolic stress. Loss or dysfunction of pericytes contributes to BBB breakdown. Low-density lipoprotein receptor-related protein 1 (LRP1), which is highly expressed in pericytes, is a critical regulator of neurovascular integrity; its downregulation activates the CypA/NF-κB/MMP-9 signaling cascade, thereby exacerbating BBB permeability. This study aimed to investigate whether the traditional Chinese medicine formula Zexieyin Formula (ZXYF) ameliorates HFD-induced cognitive impairment by targeting pericyte dysfunction. We hypothesized that ZXYF exerts neuroprotective effects by restoring pericyte-associated LRP1 expression, suppressing activation of the CypA/NF-κB/MMP-9 pathway, preserving BBB integrity, and consequently attenuating hippocampal neuronal damage. Both in vivo and in vitro models were employed to elucidate the underlying neurovascular mechanisms. In vivo, C57BL/6 mice were fed an HFD for 16 weeks to induce cognitive impairment, followed by a 4-week intervention with ZXYF; atorvastatin (ATO) served as a positive control. Cognitive function was evaluated using a battery of behavioral tests. BBB integrity was assessed by transmission electron microscopy (TEM) and Western blot analysis of the tight junction proteins ZO-1 and Claudin-5. Cerebrovascular permeability was further evaluated using sodium fluorescein extravasation assays combined with co-localization analysis with the endothelial marker CD31. Pericyte-associated LRP1 expression in the hippocampus was examined by immunofluorescent co-localization of LRP1 with the pericyte marker PDGFR-β. Activation of the CypA/NF-κB/MMP-9 signaling pathway in hippocampal tissue was analyzed by Western blotting. In vitro, mouse brain microvascular pericytes (MBVPs) were exposed to free fatty acids (FFA) to model metabolic stress. LRP1 expression and localization were assessed by confocal microscopy, and protein levels of the CypA/NF-κB/MMP-9 pathway were determined by Western blotting. An LRP1-knockdown MBVPs cell line was generated via lentiviral transduction to evaluate LRP1 dependence. HFD-fed mice exhibited pronounced cognitive deficits, which were significantly ameliorated by ZXYF treatment. TEM and Western blot analyses revealed marked BBB disruption in HFD-fed mice, characterized by ultrastructural abnormalities and reduced expression of ZO-1 and Claudin-5. Immunofluorescence demonstrated increased sodium fluorescein leakage in the hippocampus, indicating cerebrovascular damage, which was partially reversed by ZXYF. Mechanistically, confocal imaging showed a significant reduction in LRP1 expression in hippocampal pericytes of HFD-fed mice, accompanied by activation of the CypA/NF-κB/MMP-9 pathway. ZXYF intervention restored pericyte-associated LRP1 expression and suppressed pathway activation. Consistently, lentivirus-mediated LRP1 knockdown in MBVPs abolished the inhibitory effects of ZXYF on CypA/NF-κB/MMP-9 signaling, demonstrating that ZXYF-mediated pathway regulation is LRP1-dependent. This study demonstrates that ZXYF alleviates HFD-induced cognitive impairment by targeting BBB function. ZXYF restores pericyte-associated LRP1 expression, thereby inhibiting the CypA/NF-κB/MMP-9 signaling pathway, preserving BBB integrity, and protecting hippocampal neurons. These findings identify pericytes and the LRP1/CypA/NF-κB/MMP-9 axis as critical therapeutic targets in metabolic cognitive disorders and provide a novel mechanistic basis for the neuroprotective effects of traditional Chinese medicine.

ID: 42586245
Title: Targeting the hallmarks of ageing: Pharmacological challenges and breakthroughs in CRISPR delivery systems and future prospects.
Abstract: CRISPR has emerged as a next-generation gene-editing tool with the potential to target the molecular pathways associated with ageing and related disorders. It functions through RNA-guided Cas nucleases, directing DNA cleavage and utilizing the native DNA repair machinery for genetic manipulations. Advances in CRISPR technology have significantly enhanced the precision and flexibility of techniques for genome editing. The enzyme Cas9's ability to cut DNA at exact site has revolutionized genome editing by enabling accurate modifications within living eukaryotic cells. This review critically examines recent developments in CRISPR-based technologies, including Cas9, Cas12, base editing, prime editing, and CRISPR-mediated gene regulation. It highlights their rising applications in ageing research, with more emphasis on neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The review also discusses the major pharmacological and translational challenges that currently limit clinical applications, including inefficient tissue-specific delivery, off-target genome editing, immunogenicity, manufacturing complexity, and long-term safety concerns. Also, recent progress in both, viral and non-viral delivery methods are critically evaluated, including adeno-associated viruses, lentivirus vectors, lipid nanoparticles, gold nanoparticles, exosomes, electroporation, and microinjection, is thoroughly discussed to highlight their therapeutic potential and translational limitations. Current studies indicate that CRISPR-based approaches have preclinical potential for targeting important hallmarks of ageing, particularly genomic instability, telomere attrition, and mitochondrial dysfunction. Other hallmarks of ageing, such as stem cell exhaustion, epigenetic modifications, and microbiome changes, are at earlier stages of development. Overall, this review describes future strategies for developing safe, precise, and clinically translatable CRISPR-based treatments to promote healthy ageing.

ID: 42589633
Title: Exosomes as Emerging Therapeutic and Diagnostic Platforms: Biological Functions, Clinical Applications, and Translational Challenges.
Abstract: Exosomes are small membrane-bound extracellular vesicles of endosomal origin that play pivotal roles in intercellular communication by transferring proteins, lipids, metabolites, and nucleic acids. Increasing evidence indicates that these vesicles participate in diverse physiological and pathological processes, including immune regulation, tissue repair, tumor progression, neurodegeneration, and cardiovascular homeostasis. Their distinctive biological properties have consequently generated considerable interest in their development as diagnostic tools, therapeutic agents, and drug-delivery platforms. Recent progress in exosome biology and biogenesis, together with technological advances in vesicle isolation, characterization, engineering, and large-scale production, has accelerated their preclinical development and early clinical translation. Nevertheless, substantial challenges-including donor-cell heterogeneity, low production yields, insufficiently standardized protocols, and regulatory uncertainty-must be addressed before widespread clinical implementation can be achieved. This narrative review integrates current knowledge of exosome biology, diagnostic and therapeutic applications, and engineering strategies. It further examines major translational barriers and outlines future priorities for advancing exosome-based technologies toward precision medicine.

ID: 42593856
Title: A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained-Release Extracellular Vesicles for Spinal Cord Injury Repair.
Abstract: Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)-pretreated extracellular vesicles (TEVs) are enriched with anti-inflammatory and pro-regenerative factors in their cargo, while Angiopep-2 (Ang2) peptide-modified TEVs (Ang-TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)-responsive hyaluronic acid (HA)-phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on-demand Ang-TEVs release at the lesion site. This construct, Ang-TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR-664a-3p, which suppressed PIK3CA to attenuate PI3K-AKT-mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli-responsive biomaterials, this strategy provides an elegant blueprint for engineering EV-based therapies to repair the injured central nervous system.

ID: 42595239
Title: Decoding TREM2: A microglial receptor governing the fate of myelin.
Abstract: Impaired myelin integrity and defective myelin regeneration represent core pathological features shared by central nervous system (CNS) diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), ischemic cerebral white matter lesions and spinal cord injury (SCI). Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is highly enriched in central resident microglia; it is also expressed by border-associated macrophages and lesion-infiltrating monocyte-derived macrophages, rather than being restricted to parenchymal microglia, acting as a key membrane receptor regulating microglial immune balance, lipid transport, lysosomal degradation and cell polarization. Existing studies demonstrate that TREM2 binds various ligands including myelin lipid debris, apolipoprotein E (APOE) and apoptotic cell components, then activates multiple DNAX-activating protein of 12 kDa (DAP12)-dependent signaling cascades: spleen tyrosine kinase (SYK)-phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma 2 (PLCγ2), beta-catenin and transcription factor EB (TFEB). These pathways jointly clear myelin debris, remodel cholesterol circulation, restrain pro-inflammatory microenvironment and promote oligodendrocyte precursor cell (OPCs) differentiation, exerting bidirectional functions in physiological myelin homeostasis, acute injury response and chronic repair. This narrative review summarizes TREM2's gene and protein structure, ligand recognition modes and full signal transduction network. It illustrates the molecular mechanisms of TREM2 in myelin maintenance, debris clearance and regeneration, compares its distinct pathological roles in various demyelinating diseases, and concludes translational strategies including TREM2 agonism, downstream pathway intervention and biomarker exploitation. Furthermore, this narrative review analyzes unsolved core scientific issues and puts forward research routes for mechanistic research and clinical transformation, offering systematic theoretical basis for targeted drug development against demyelinating encephalopathies.

ID: 42603243
Title: Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.
Abstract: Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.

ID: 42603521
Title: Generation of a human induced pluripotent stem cell line (HEBHMUi019-A) from a 67-year-old male Alzheimer's patient with APOE-ε4/ε4 genotype.
Abstract: Apolipoprotein E (apoE), encoded by the polymorphic APOE gene, plays a key role in lipid transport and metabolism. The three major APOE alleles are ε2, ε3, and ε4, with ε4 being the strongest genetic risk factor for late-onset Alzheimer's disease. We generated human induced pluripotent stem cells from peripheral blood mononuclear cells of a 67-year-old male patient with Alzheimer's disease carrying the APOE ε4/ε4 genotype. The generated cell line displayed typical iPSC morphology, a normal karyotype, trilineage differentiation potential, and pluripotency-marker expression, providing a resource for investigating APOE ε4-associated disease mechanisms and preclinical therapeutic screening.

ID: 42608571
Title: Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.
Abstract: Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.

ID: 42609050
Title: Characterization of [18F]SMBT-1 binding substrates in Alzheimer's disease and related disorders: A postmortem biochemical and immunohistochemical study.
Abstract: Neuroimaging studies report associations of amyloid beta (Aβ) positron emission tomography (PET) with [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1), a novel reactive astrogliosis surrogate radiotracer with high affinity for monoamine oxidase B (MAO-B) in Alzheimer's disease (AD). Postmortem association of [18F]SMBT-1 binding with pathology of AD and non-AD tauopathies is undefined. [18F]SMBT-1 binding, [3H]Pittsburgh compound B ([3H]PiB) binding, and MAO-B activity assays in brain homogenates, with [18F]SMBT-1 autoradiography and MAO-B immunoreactivity in relation to glial fibrillary acidic protein (GFAP), major histocompatibility complex II (MHC-II), Aβ, phosphorylated tau, cyano-Pittsburgh compound B (cyano-PiB), and X-34 on brain sections from AD, non-AD tauopathies, and nondemented controls. [18F]SMBT-1 binding correlated with MAO-B activity and [3H]PiB binding, with highest levels in AD. [18F]SMBT-1 autoradiography corresponded to MAO-B/GFAP-immunoreactive astrocytes associated with Aβ deposits in plaques and vasculature, more closely than to tau pathology. [18F]SMBT-1 binding and MAO-B activity in non-AD tauopathies partially overlapped controls and AD, with MAO-B/GFAP-immunoreactive astrocytes in areas with tau pathology. [18F]SMBT-1 is a promising biomarker of MAO-B reactive astrocytes in AD and non-AD tauopathies.

ID: 42614391
Title: Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.