ID: 32152337
Title: APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice.
Abstract: The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4's role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

ID: 34611141
Title: APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.
Abstract: Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

ID: 42602088
Title: Electroacupuncture improves neurocognitive impairment induced by chronic sleep deprivation: an experimental study based on hippocampal neurogenesis and synaptic plasticity.
Abstract: Normal sleep rhythms are crucial for hippocampus-dependent advanced cognitive functions. Chronic sleep deprivation (CSD) impairs hippocampal neurogenesis and structure, leading to neurocognitive deficits. Electro-nape-acupuncture (ENA) at bilateral Fengchi (GB20) and Gongxue (Extra) is a specialized acupuncture technique for treating insomnia, amnesia, and other brain-originated diseases. This study aims to investigate whether ENA improves CSD-induced cognitive impairment by regulating neurogenesis and synaptic plasticity in the hippocampus. The modified multi-platform water environment method was used to establish the CSD model. Electroacupuncture or sham electroacupuncture was used to treat bilateral cervical acupoints (Fengchi and Gongxue) for 20 min, once a day for 14 days. The Morris water maze experiment evaluated spatial learning and memory in rats, and the new object recognition experiment evaluated recognition memory. Immunofluorescence (IF) staining and Western Blot (WB) were used to detect the expression levels of the hippocampal neurogenesis markers, doublecortin (DCX) and Ki-67. Golgi-Cox staining and transmission electron microscopy were used to observe the changes in neurons and synaptic plasticity in the dentate gyrus (DG) of the hippocampus. Neurocognitive impairment induced by CSD is associated with abnormal changes in hippocampal neurogenesis and synaptic plasticity. The results of IF and WB showed that the protein expressions of DCX and Ki-67 in the hippocampus of CSD rats were significantly decreased. Transmission electron microscopy revealed that in the DG region of the hippocampus of CSD rats, the synaptic density and the thickness of the postsynaptic density membrane decreased, while the synaptic cleft width increased. Golgi staining showed that the density of dendritic spines in the DG area of the hippocampus in CSD rats decreased significantly, especially mushroom-shaped dendritic spines. ENA can enhance spatial learning and memory, as well as recognition memory, induced by CSD, and effectively reverse the abnormal changes in neurogenesis and synaptic plasticity in the DG region of the hippocampus. In male Wistar rats, ENA improves neurocognitive function by promoting neurogenesis in the hippocampal dentate gyrus and restoring synaptic plasticity, thereby reconstructing neural memory circuits. ENA therapy offers a new strategy for treating cognitive impairments related to chronic sleep deprivation in males, and holds potential significance for the clinical management of cognitive impairment diseases.

ID: 42604557
Title: Reprogramming lineage-traced Müller glia for robust proliferation and neurogenesis in adult mammalian retinas.
Abstract: The therapeutic potential of adeno-associated virus (AAV)-mediated one-step glia-to-neuron conversion has been challenged following rigorous lineage-tracing analyses. In zebrafish, Müller glia (MG) serve as retinal stem cells to replenish lost neurons after injury. In contrast, mammalian MG do not spontaneously re-enter the cell cycle, and limited neurogenesis occurs in response to neurotoxic injury. Here, we demonstrate that activation of FGF2/MAPK signaling, following AAV-mediated gene transfer of Ascl1, effectively stimulates lineage-traced MG to undergo robust cell-cycle re-entry in adult mice, independent of neurotoxic injury. With the addition of retinoic acid, this approach further reprograms a significant proportion of proliferative MG-derived progenitor-like cells into regenerative states, driving enhanced in vivo neurogenesis. Using multiplex techniques, we reveal distinct phases of cell fate transitions during in vivo MG-derived neurogenesis. This approach provides a two-step strategy for inducing MG proliferation and subsequent MG-derived neurogenesis, which may represent a potent avenue toward retinal regeneration.

ID: 42612866
Title: TMEM175 deficiency impairs autophagic degradation and alleviates mitochondrial oxidative damage in cardiomyocytes through AMPK activation.
Abstract: Transmembrane protein 175 (TMEM175) is a lysosomal proton-activated and proton-selective channel critical for regulating lysosomal membrane potential and acidity. However, its role in cardiomyocyte physiological and stress response remains unclear. Here, we investigated the function of TMEM175 in mitochondrial homeostasis using H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVMs) under physiological conditions and during hydrogen peroxide (H2O2)-induced oxidative stress. Under physiological conditions, genetic knockout of TMEM175 impaired mitochondrial respiration, reduced mitochondrial superoxide, and attenuated autophagic clearance. In contrast, under H2O2-induced stress, TMEM175 deletion significantly alleviated mitochondrial dysfunction and cell death, despite autophagic flux being primarily stalled at the degradation stage. Mechanistically, TMEM175 deficiency activated AMP-activated protein kinase (AMPK), and silencing AMPK reversed the cytoprotective effects of TMEM175 deletion against H2O2 injury. Pharmacological inhibition of TMEM175 with 2-phenylpyridin-4-ylamine (2-PPA) in H9c2 and NRVMs recapitulated key phenotypes observed in genetic knockout models. Furthermore, 2-PPA improved cardiac function and attenuated histopathological injury in myocardial infarction mice. Together, these findings reveal a dual role for TMEM175: it maintains lysosomal-mitochondrial communication under basal conditions, yet its inhibition protects against oxidative stress primarily through AMPK activation. This study identifies TMEM175 as a novel lysosomal regulator of cardiac mitochondrial resilience and highlights its potential role in the cellular response to oxidative injury in cardiomyocytes.

ID: 42613533
Title: Ganglioside Functions in Extracellular Vesicles as Revealed by Single-Particle Tracking.
Abstract: Extracellular vesicles play roles as critical mediators of cell-cell communications. We recently discovered that ganglioside content in extracellular vesicles was approximately 30 times higher than in cells, and GM1 in extracellular vesicles specifically binds to laminin. In this chapter, we describe a method to prepare cells expressing specific gangliosides and introduce in vitro experiments to evaluate the binding ability of extracellular vesicles and liposomes containing gangliosides to the extracellular matrix.

ID: 42613696
Title: An Innovative Strategy for Treating Neurodegenerative Disorders through Exosome-based Smart Delivery Systems: A Comprehensive Review.
Abstract: Alzheimer's and Parkinson's diseases are devastating brain disorders. The complex pathophysiology of the diseases and the lack of effective treatments have left them almost unexplored and untreatable. One potential approach to PD and AD therapy development is through exosomes, a delivery system that can be translated from innovative delivery techniques into clinical use. These exosome-based therapeutics will require thorough testing, research-driven refinement of engineering methods, and collaboration among scientists, clinicians, and industry to develop exosome therapeutics for clinical use. This review explores the biological properties of exosomes, recent engineering advances to improve their therapeutic potential, and new methods to leverage their versatility for selective delivery of remedial agents to the brain. In addition, preclinical evidence demonstrates that exosomes can modulate amyloid-β aggregation, α-synuclein pathology, neuroinflammation, and mitochondrial dysfunction. Yet difficulties related to mass production, maintaining quality, and obtaining regulatory approvals to bring them into clinical practice remain significant limiting factors. The authors point out the therapeutic advantages and drawbacks of exosome-based drug delivery systems. Besides, it provides a roadmap for harnessing these methods effectively as medical interventions for Alzheimer's and Parkinson's disorders, thereby promoting more studies in the area. Finally, we outline a conceptual model for translating novel exosome-based delivery methods into clinically applicable treatment modalities for Alzheimer's and Parkinson's diseases, thereby encouraging continued exploration in this promising field of research.

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.

ID: 42614552
Title: Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes.
Abstract: Depression represents a multifaceted neuropsychiatric disorder distinguished by disruptions in cerebral energy metabolism, neurotransmitter communication, neuroplasticity, and cognitive processes. An increasing body of literature indicates that integrative non-pharmacological interventions aimed at metabolic and neurochemical pathways may present promising adjunctive strategies for ameliorating depressive manifestations and concomitant cognitive impairments. This review explores the prospective combined effects of creatine supplementation, branched-chain amino acids (BCAAs), and physical exercise as a multimodal bioenergetic intervention for the management of depression. Creatine is pivotal in maintaining neuronal energy equilibrium via the phosphocreatine system, thereby facilitating mitochondrial functionality and adenosine triphosphate availability within neural cells. BCAAs may influence central fatigue and exercise performance through competitive inhibition of tryptophan transport across the blood-brain barrier. Importantly, this mechanism primarily reflects acute exercise-related serotonergic responses associated with central fatigue and should not be considered mechanistically equivalent to the chronic serotonergic dysfunction observed in major depressive disorder. Accordingly, within the context of depression, BCAAs are discussed as indirect modulators of mental health outcomes through their effects on fatigue perception, exercise tolerance, and adherence to physical activity, rather than as direct serotonergic antidepressant interventions. Concurrently, consistent engagement in physical exercise activates critical neuroplasticity-associated signaling pathways, which are instrumental in promoting hippocampal neurogenesis and enhancing stress resilience. Emerging empirical evidence derived from both experimental and clinical investigations suggests that the combined application of these interventions may exert complementary influences on brain bioenergetics, neuroplasticity, exercise capacity, and cognitive function. Collectively, this integrative paradigm highlights the potential of creatine supplementation, BCAAs, and physical exercise to support depression-related outcomes through distinct yet complementary mechanisms involving bioenergetic regulation, enhanced exercise capacity, neuroplastic adaptations, and improved cognitive and emotional functioning.

ID: 42614677
Title: Bidirectional crosstalk between the nervous system and the tumour microenvironment: mechanisms, feedback loops and therapeutic opportunities.
Abstract: The nervous system is increasingly recognized as an active and integral component of the tumour microenvironment (TME), rather than a passive bystander affected by tumour invasion. Emerging evidence indicates that neural inputs shape tumour behaviour through both direct and indirect mechanisms. Neurotransmitters, neuropeptides and neurotrophic factors act on tumour cells, stromal cells, endothelial cells and immune cells to regulate proliferation, invasion, metastasis, angiogenesis, metabolic reprogramming and immune evasion. In parallel, the TME feeds back to the nervous system through inflammatory mediators, extracellular vesicles, axon guidance molecules and metabolic signals, thereby driving axonogenesis, tumour innervation, Schwann cell reprogramming, neuronal hyperexcitability and synaptic remodelling. These reciprocal interactions establish dynamic neuro-immune-metabolic feedback loops that sustain tumour progression and therapeutic resistance. Particularly in glioma and other highly innervated malignancies, activity-dependent neuron-tumour communication further highlights the functional integration between neural circuits and cancer. In this Review, we summarize the structural and molecular basis of neural components within the TME, discuss neurotransmitter receptor-mediated signalling and indirect regulation of immune, vascular, stromal and metabolic niches, and outline how tumour-derived signals remodel peripheral and central neural systems. We further highlight emerging therapeutic opportunities targeting β-adrenergic signalling, neurotrophin pathways, extracellular vesicle-mediated tumour innervation, Schwann cell-associated perineural invasion circuits, and neuron-tumour synaptic coupling. Finally, we discuss current translational challenges, including tumour-type heterogeneity, context-dependent neural effects, evidence-level heterogeneity and the need for spatially resolved biomarkers, and propose that incorporating the neural dimension into future mechanism-guided studies may inform biomarker-stratified trials and symptom-oriented interventions, with the long-term goal of improving both tumour control and neurological outcomes.

ID: 42616073
Title: Transcriptomic profiling and structural characterization reveal UQCRC1 and COX4I1 as key mitochondrial regulators associated with oxidative stress in multiple sclerosis.
Abstract: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system characterized by inflammatory demyelination, progressive neurodegeneration, and irreversible disability. While immune dysregulation initiates disease pathology, the molecular mechanisms linking chronic inflammation to mitochondrial dysfunction and oxidative stress remain incompletely understood. An integrative, multi-layered systems biology approach was applied to four independent RNA-sequencing datasets derived from MS white matter lesions, lesion-border microglia/macrophages, and Epstein-Barr virus-associated B cells. Differential gene expression analysis was combined with targeted prioritization of mitochondrial and oxidative stress-related genes using curated databases. Protein-protein interaction network construction, hub gene identification, Gene Ontology, and KEGG pathway enrichment analyses were performed to identify prioritized mitochondrial genes and enriched biological pathways. Independent validation was conducted using CNS-specific TNMplot expression profiling, and prognostic relevance was assessed through immunogenomic survival analysis. Structural and functional impacts of prioritized variants were evaluated using in silico pathogenicity prediction, protein stability analysis, secondary structure modeling, and three-dimensional structural assessment, including MutPred2 and HOPE analyses. Transcriptomic integration revealed consistent dysregulation of gene expression profiles across all datasets. Functional enrichment analyses identified mitochondrial oxidative phosphorylation as the most significantly enriched biological process, suggesting an association between altered mitochondrial respiratory pathways and MS-related molecular signatures. Network and enrichment analyses consistently prioritized UQCRC1 and COX4I1 as key mitochondrial hub genes, corresponding to core subunits of respiratory chain complexes III and IV, respectively. These genes were recurrently enriched across biological processes, cellular components, molecular functions, and neurodegeneration-related pathways. CNS-restricted validation confirmed their differential expression, while immunogenomic analysis demonstrated that higher expression levels were associated with improved overall survival. Variant-level analysis identified UQCRC1 (G235R, L197R) and COX4I1 (G155C, P152R) as deleterious substitutions predicted to destabilize protein structure, disrupt domain interactions, and impair electron transport efficiency. Functional predictions further indicated altered catalytic activity, metal binding, and structural integrity, supporting their potential functional relevance to mitochondrial biology. This study demonstrates that mitochondrial respiratory chain-related pathways, particularly those involving complexes III and IV, are consistently associated with the transcriptomic alterations observed in multiple sclerosis. UQCRC1 and COX4I1 emerged as prioritized mitochondrial hub genes supported by integrated transcriptomic, network, prognostic, and structural analyses. These findings provide evidence that mitochondrial bioenergetics and redox homeostasis may contribute to MS pathobiology and warrant further experimental investigation as potential biomarkers and therapeutic targets.

ID: 42616755
Title: When muscles matter in SORD neuropathy.
Abstract: Biallelic pathogenic variants in SORD (Sorbitoldehydrongenase gene), encoding sorbitol dehydrogenase, are a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (CMT2). Recent evidence suggests direct involvement of skeletal muscle in addition to peripheral nerve degeneration. We investigated muscle biopsies from 4 genetically confirmed CMT-SORD patients using an integrative approach. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, ie, non-specific neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum (SR). Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement and immunomodulatory factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodeling. Despite mitochondrial vulnerability, serum studies indicated that GDF-15 and FGF-21 did not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as intrinsic myopathic features of SORD-related CMT2. They indicate the need for therapeutic strategies targeting both neuronal and muscular compartments.