ID: 42039388
Title: Parkinson's disease-linked D620N mutation selectively alters the brain-specific protein interactome of VPS35.
Abstract: Mutations in several genes are known to cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene linked to late-onset, autosomal dominant PD. VPS35 encodes a core subunit of the retromer complex which functions in endosomal sorting and recycling. It remains unclear how the pathogenic D620N mutation in VPS35 disrupts retromer function to induce neurodegeneration in PD. Using cell- and rodent-based models expressing D620N VPS35, we performed interactome proteomics to identify alterations underlying the pathogenic effects of D620N VPS35 in PD. Using overexpression of VPS35 variants in HEK-293T cells, we conducted tandem affinity purification (TAP) or co-immunoprecipitation (co-IP) with protein chemical crosslinking to determine the native and non-native protein interactomes of wild-type (WT) and D620N VPS35, respectively. Notably, we can confirm the reduced interaction of D620N VPS35 with components of the WASH complex. Additionally, using a viral-mediated gene transfer model of human D620N VPS35 overexpression in adult rat brain, we identify the first brain-specific protein interactome of VPS35. These overexpression models reveal remarkably similar interaction profiles of WT and D620N VPS35, suggesting that the D620N mutation has a subtle effect on the overall VPS35 protein interactome. We also conducted proteomic analysis of brain tissue from a D620N VPS35 knockin (KI) mouse model that expresses VPS35 at endogenous levels. Using co-IP from hemi-brain or striatal extracts of WT and D620N VPS35 KI mice, we reveal a high degree of similarity between the brain interactomes of WT and D620N VPS35, further suggesting a subtle effect of the D620N mutation on VPS35 protein interactions. Notably, in both hemi-brain and striatum, we find a selective decrease in the interaction of two known interactors, TBC1D5 and VPS29, with D620N VPS35. We also performed global proteomic analysis of striatal tissue from D620N VPS35 KI mice and reveal a high degree of similarity between WT and D620N, further suggesting a subtle effect of this mutation. Together, our study provides a comprehensive evaluation of the VPS35 protein interactome and reveals a selective effect of the PD-linked D620N mutation in mammalian cells and brain. Our study provides key insight into the mechanisms of retromer dysfunction in VPS35-linked PD.

ID: 42043050
Title: Interference of Large Clostridial Glucosyltransferases with the Endolysosomal Pathway: Toxin-Induced Imbalance of Early Endosomes, Functional Lysosomes and Autophagosomes.
Abstract: Toxin A and B from Clostridioides difficile are the main pathogenicity factors for clinical symptoms of C. difficile infections. Receptor-mediated endocytosis and endosomal escape are required for targeting substrate proteins of the Rho-GTPase family. We previously reported that Toxin B (TcdB) affects endo-lysosomal transport and autophagic flux of target cells. These effects are independent from pathogenic Rho inhibition. Here, we aimed at further characterization of this event by immunofluorescent characterization of the vesicular structures that are affected. We found large aggregates of damaged endolysosomal structures positive for EEA1, LAMP1, CHMP4B and TcdB, as well as an increase in perinuclear concentration of non-mature autophagosomes (amphisomes) positive for SQSTM, Rab7, and LC3B. We investigated whether Rab7, a regulator of late endosome transport, is causative for decreased lysosome function. Although TcdB induced an increase in active Rab7, as tested by an RILP pull-down assay, inhibition of Rab7 did not prevent TcdB-induced decrease in cathepsin D as a surrogate for lysosome dysfunction. It also indicates that the observed increase in Rab7 positive amphisomes is secondary to lysosomal dysfunction. By applying an autoproteolytic deficient mutant of TcdB we proved that the release of the glucosyltransferase domain is mandatory for triggering all of these effects. This suggests that after membrane perforation the toxin remnants leave an open leak in endolysosomes affecting ion homeostasis. Investigation of all large clostridial glucosyltransferases and other toxins revealed lysosomal dysfunction as a general effect of many but not of all toxins that integrate into the endosome membrane.

ID: 42092489
Title: HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation.
Abstract: People living with HIV develop persistent neurocognitive impairment despite viral suppression through incompletely defined mechanisms. HIV-1 Tat disrupts VAPB-PTPIP51 coupling at mitochondria-associated ER membranes via PTPIP51 tyrosine phosphorylation, causing VAPB relocalization away from MAMs, a causal mechanism established in our prior work. Here, we define the downstream metabolic consequences and establish VAPB as the critical determinant of neuronal lipid pathology. Lipidomic profiling identified triglycerides as the dominant altered species, comprising polyunsaturated forms normally destined for membrane synthesis or mitochondrial oxidation, consistent with membrane catabolism rather than de novo lipogenesis. Targeted metabolomics revealed bioenergetic collapse consistent with impaired mitochondrial oxidative function. The resulting lipid imbalance, including lipid droplet accumulation, produced secondary organellar dysfunction, including Golgi dispersal and ER stress. Critically, Tat failed to induce lipid droplet accumulation in shRNA-VAPB cells, while PTPIP51 silencing had no such protective effect, establishing that VAPB relocalization is the obligate trigger. Guanosine supplementation reduced lipid droplet accumulation, suggesting a link to bioenergetic failure that warrants further investigation. In postmortem HIV-infected frontal cortex, VAPB was paradoxically elevated yet correlated with worsening dementia severity, consistent with transcriptional upregulation that cannot overcome posttranslational blockade of VAPB-MAM localization. The polyunsaturated triglycerides, depleted plasmalogens, and elevated ceramides documented here closely parallel lipid signatures reported in PLWH with cerebrovascular complications, implicating Tat-driven lipid dysregulation as a candidate mechanism for the incompletely explained elevation in stroke risk in this population.

ID: 42135946
Title: The autophagic and non-autophagic functions of the S. cerevisiae PROPPIN Hsv2.
Abstract: Autophagosome formation depends on PtdIns3P, its presence is deciphered by PROPPINs, a family of β-propellers, which in yeast consists of Atg18, Atg21 and Hsv2 and in mammals of WIPI1, WIPI2, WDR45B/WIPI3 and WDR45/WIPI4. While Atg18 is required for scaffolding the Atg2-Atg9 complex, which mediates non-vesicular membrane transport to the phagophore, Atg21 organizes the Atg8 lipidation machinery. Atg18 further acts as part of a retromer complex in vacuole fragmentation. So far, the function of Hsv2 remained elusive. Here we show that Hsv2 is required for autophagy of large cargos such as the fatty acid synthase complex (FAS) and ribosomes. We further found that Hsv2 interacts with the key retromer component Vps35 and mediates vacuole fission cooperatively with Atg18. Interestingly, the residues for interaction of Hsv2 with Atg2 and Vps35 are distinct from those of Atg18. Hsv2 is known to affect the biogenesis of the spore wall, which prompted us to include diploid cells in our analyses. We found that Hsv2 interacts with the SNARE Pep12, and that Pep12 mislocalized to the vacuole in diploid but not haploid hsv2∆ cells. This suggests a role of Hsv2 in protein sorting in diploid cells. The loop 6C/D of PROPPINs partially inserts into membranes causing their bending. We found that the membrane bending activity of Hsv2 is required for vacuole fragmentation and sorting in diploids but not for its autophagic function. Mutations in WDR45/WIPI4, the presumed mammalian homolog of Hsv2 cause the neurodegenerative disease BPAN, our study thus also helps to understand its underlying principles.Abbreviations: CSC: cargo specific complex, FAS: fatty acid synthase, PAS: phagophore assembly site; PROPPIN: beta-propeller that binds phosphoinositides.

ID: 42138513
Title: African swine fever virus I10L protein inhibits autolysosome formation by disrupting RAB7-HOPS complex-dependent SNARE complex assembly.
Abstract: Macroautophagy/autophagy serves as a crucial cellular defense mechanism against invading pathogens. However, viruses have evolved diverse strategies to evade or even exploit autophagy for their own replication. In this study, we reveal that the African swine fever virus (ASFV)-encoded I10L protein suppresses autophagy by blocking autophagosome-lysosome fusion. Mechanistically, I10L directly interacts with the endolysosomal RAB GTPase RAB7, a master regulator of vesicle docking at late endosomes and lysosomes. This interaction competitively prevents RAB7 from binding to VPS39, a core component of the homotypic fusion and vacuole protein sorting (HOPS) complex. Consequently, I10L disrupts the assembly of the STX17-SNAP29-VAMP8 SNARE complex, which is essential for autophagosome-lysosome fusion. ASFV infection thus induces autophagosome accumulation, whereas I10L deletion reverses this effect and attenuates viral replication in primary macrophages. Our findings uncover a novel immune evasion strategy by which ASFV subverts lysosomal degradation through RAB7-HOPS axis manipulation, providing both mechanistic insights into viral pathogenicity and potential therapeutic targets for antiviral development.Abbreviations: ASFV: African swine fever virus; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PAMs: primary alveolar macrophages; RAB7: RAB7, member RAS oncogene family; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TM: transmembrane domain; VAMP8: vesicle associated membrane protein 8; VPS39: VPS39 subunit of HOPS complex; VPS41: VPS41 subunit of HOPS complex; YKT6: YKT6 vesicular SNARE protein.

ID: 42183611
Title: Mammalian lysophagy: mechanisms and pathophysiological implications.
Abstract: Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.Abbreviations: ALR, autophagic lysosome reformation; ALS, amyotrophic lateral sclerosis; ATG8, mammalian Atg8-family protein; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; LAMPs, lysosome associated membrane proteins; LIR, LC3-interacting region; LLOMe, L-leucyl-L-leucine methyl ester; LMP, lysosomal membrane permeabilization; PITT, phosphoinositide-initiated membrane tethering and lipid transport; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns4P, phosphatidylinositol-4-phosphate; ROS, reactive oxygen species; V-ATPase, vacuolar-type H+ -ATPase.

ID: 42215790
Title: The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.
Abstract: Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.

ID: 42222161
Title: Berbamine sensitizes hepatocellular carcinoma to chemotherapy by inhibiting autophagy via modulating SIRT1-mediated acetylation.
Abstract: Chemoresistance driven by pro-survival autophagy remains a major obstacle in hepatocellular carcinoma (HCC) treatment. Berbamine (BBM), a natural alkaloid with a favorable clinical safety profile, shows potential as an autophagy inhibitor, yet its precise mechanism in HCC remains unclear. Using CCK-8, colony formation, and apoptosis assays, we first demonstrated that BBM synergistically enhanced the efficacy of multiple chemotherapeutic agents (5-FU, Sorafenib, Paclitaxel) against HCC cells in vitro. This synergistic effect was confirmed in an H22 xenograft mouse model in vivo. To investigate the mechanism, we monitored autophagic flux and lysosomal function. Western blot and immunofluorescence analyses revealed that BBM treatment led to the concurrent accumulation of LC3-II and p62, indicating a blockade of late-stage autophagic flux. Further experiments, including LysoTracker staining and assessment of lysosomal protease levels, showed that BBM impaired both autophagosome-lysosome fusion and lysosomal acidification. Mechanistically, we found that BBM downregulated SIRT1 protein expression and reduced the intracellular NAD+/NADH ratio, thereby inhibiting SIRT1 deacetylase activity. This suppression impaired the nuclear translocation and function of the key autophagy transcription factor TFEB, leading to decreased levels of its downstream targets RAB7, CTSB, and CTSD. Crucially, rescue experiments using specific agonists revealed that SIRT1 activation completely reversed all BBM-induced effects, including autophagic flux blockade and downstream protein suppression, whereas TFEB activation only partially rescued the expression of RAB7, CTSB, and CTSD without restoring autophagic flux. This establishes SIRT1 as the primary upstream regulator in this pathway. Our study identifies BBM as a novel autophagy inhibitor that targets the SIRT1-TFEB axis to disrupt autolysosomal fusion and degradation, and nominates it as a promising combinational agent to overcome chemoresistance in HCC.

ID: 42223785
Title: Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.
Abstract: Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ1-42 oligomer-enriched assemblies (oAβ1-42), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.

ID: 42251940
Title: Targeted degradation of intracellular organelles: Strategies and implications.
Abstract: Organelle dysfunction is increasingly recognized as a primary driver of neurodegeneration, metabolic disorders, and cancer. The selective elimination of these organelles is primarily mediated by the autophagy-lysosome pathway. Targeted organelle degradation (TOD) has thus emerged as a powerful strategy to harness and redirect this machinery, enabling the selective clearance of organelles through engineered cargo recognition and lysosomal delivery. In this review, we aim to establish a mechanism-driven classification framework for TOD. We comprehensively survey current strategies and systematically integrate representative modalities, including autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), nanoparticle-based organelle targeting chimeras (NanoTACs), and related platforms within this framework. Key experimental strategies for assessing degradation efficiency are critically compared, with a particular focus on mitochondria and lipid droplets as well-developed case studies. Finally, we discuss the potential for expanding TOD to other organelles such as the endoplasmic reticulum and Golgi apparatus, and we highlight key challenges and future directions to drive continued advancement in the field.

ID: 42276196
Title: Septins regulate kinase-inhibitor induced micron-scale vacuolation.
Abstract: Several kinase inhibitors including pyridinyl imidazole class p38 MAPK inhibitors and specific PIKFYVE inhibitors have been shown to induce endosomal swelling and micron-scale vacuolation, by inhibiting a PIKFYVE-dependent pathway. We performed a screen to identify small molecule modulators of micron-scale vacuolation and identified septin inhibitor Forchlorfenuron (FCF) as an inhibitor of vacuolation. FCF inhibited vacuolation induced by SB202190, PIKFYVE inhibitors and VE-821. shRNA-mediated depletion of SEPT9 suppressed kinase inhibitor-induced vacuolation, while SEPT7 knockdown did not affect vacuolation. Similar results were obtained when experiments were performed using penfluridol as another modulator of septin cytoskeleton. The kinase-inhibitor induced vesicles, identified as swollen RAB7+ late endosomes colocalized with CD63 and FCF treatment led to the loss of these RAB7-labelled micron-scale vacuoles. FCF not only abrogates vacuole formation but also suppresses resolution of vacuoles upon SB202190 withdrawal. However, septin filaments do not colocalize with the vacuoles. Unlike bafilomycin, which inhibits vacuolation with parallel blockade of autophagic proteolysis, FCF mediated suppression of vacuoles doesn't involve accumulation of autophagy markers. The role of septins in micron scale vacuolation may be linked to their role in endosome maturation and septins may contribute towards the cell-type specificity of micron-scale vacuolation.

ID: 42285981
Title: Reactive astrocytes mediate toxicity in iPSC derived dopaminergic neurons.
Abstract: Neuroinflammation is a hallmark of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein and the death of dopaminergic neurons in the substantia nigra. Mutations in GBA are a common risk factor for PD, which can lead to lipid metabolism dysfunction, autophagy/lysosomal dysregulation, as well as the disruption of other cellular functions. In this study, we investigated the impact of the GBA-N370S mutation and astrocytic reactivity on α-synuclein pathology and neurotoxicity. To investigate the impact of reactive astrocytes on Parkinson's disease pathology, we employed iPSC-derived midbrain astrocyte and dopaminergic neuron co-cultures from control and GBA-N370S donors, as well as primary mouse midbrain astrocyte cultures and transcriptomic assays to examine the response of astrocytes to Tumor Necrosis Factor-α (TNFα) and Interferon-γ (IFNγ). We show that upon inflammatory stimuli astrocytes become reactive, leading to extensive transcriptional changes. RNAseq and experimental validation revealed that calcium transport and homeostasis were severely dysregulated, and functional studies confirmed that GBA-N370S astrocytes exhibited increased calcium release when treated with cytokines. We further explored the impact of inflammation on astrocytic neurosupport in an iPSC-derived dopaminergic neuron and astrocyte co-culture model finding that combined treatment of TNFα, IFNγ and α-synuclein pre-formed fibrils (PFFs) led to neurotoxic effects, suggesting that TNFα and IFNγ-activated astrocytes mediate α-synuclein PFF toxicity. Taken together, these data provide evidence of reduced neurosupport in both control and GBA-N370S iPSC-derived midbrain astrocytes exposed to inflammatory cytokines, suggesting a role for reactive astrocytes in PD pathology.

ID: 42321809
Title: Bacteria-derived glutarate mitigates Alzheimer's disease model pathology through autophagy-lysosomal pathway.
Abstract: Probiotics exert neuroprotective effects against Alzheimer's disease (AD) by modulating gut-brain axis pathways, though disease-modifying therapies remain unavailable. Our study revealed that Escherichia coli (E. coli) strain HB101 ameliorated AD-related phenotypes in Caenorhabditis elegans‌ (C. elegans) models, including learning deficits, neurodegeneration, and paralysis. Mechanistically, HB101 reduced amyloid-β (Aβ) aggregation by enhancing lysosomal activity, autophagy, and mitochondrial/endoplasmic reticulum unfolded protein responses (UPRmt/UPRer). Specifically, HB101 activated UPRmt via atfs-1 and sphk-1, and UPRer through pek-1. Metabolomic screening pinpointed glutarate as a bioactive metabolite that mitigates AD-related pathology through lysosomal activation and autophagy promotion.

ID: 42346109
Title: Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.
Abstract: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear. To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention. Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology. Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.

ID: 42352457
Title: Engineered Exosomes in Precision Neuro-Oncology: Mechanisms, Therapeutics, and Translational Challenges.
Abstract: Exosomes are small vesicles released by cells that have attracted growing interest as drug delivery vehicles, particularly for brain diseases, where getting therapeutics across the BBB remains a fundamental problem. While conventional platforms such as liposomes, polymeric nanoparticles, and viral vectors often suffer from immune clearance and poor brain accumulation, engineered exosomes leverage natural cellular transport mechanisms to cross the BBB, protect cargo from degradation, and enable biocompatible interactions with target cells. This review takes a mechanistic and translational look at how exosomes are being engineered for CNS disorders, with a particular focus on glioblastoma. We cover exosome biogenesis through ESCRT-dependent and ESCRT-independent pathways, and how the competition between Rab27-driven secretion and Rab7-driven lysosomal degradation determines how many exosomes a cell releases, which has direct consequences for therapeutic production. We then discuss cargo loading strategies, from genetic approaches where donor cells are engineered to package specific molecules during biogenesis to physical methods like electroporation and sonication applied to isolated vesicles, alongside surface modification techniques for directing exosomes toward specific cell types. In glioblastoma, engineered exosomes have shown real promise for delivering chemotherapeutics across the BBB, targeting glioma stem cells, enabling CRISPR-based gene editing, and functioning as combined treatment and imaging tools. Applications in stroke and neurodegenerative diseases, where engineered exosomes carrying microRNAs and neuroprotective cargo have produced encouraging preclinical results, are also discussed. Scalable manufacturing and consistent targeting remain the hardest unsolved problems, and we outline emerging approaches including bioreactor-based production, programmable cargo loading, and patient-specific exosome design that are beginning to address these gaps. Overall, the progress reviewed here suggests that engineered exosomes are moving from an interesting biological concept toward a practically viable platform for CNS drug delivery.

ID: 42370259
Title: Synaptojanin1 regulates synaptic dopamine release and axonal integrity via retromer-dependent endosomal sorting.
Abstract: Synaptic dysfunction is increasingly recognized as an early feature of Parkinson's disease (PD); however, synaptic mechanisms contributing to early dopamine release defects and neurodegeneration remains poorly understood. Here we identify a presynaptic endosomal-dependent mechanism supporting dopamine release and axonal integrity. Loss of the PD-associated lipid enzyme Synaptojanin1 impairs dopamine release due to endosomal retention of the dopamine D2 autoreceptor and dopamine transporter (DAT). Conditional deletion of Synaptojanin1 in mouse dopamine neurons results in endosomal swelling within striatal DAT clusters and PD-like locomotor deficits. Mechanistically, Synaptojanin1 remodels endosomal phosphatidylinositol 4-phosphate to facilitate the recruitment of the PD-associated retromer component VPS35. Notably, overexpressing VPS35 rescues presynaptic sorting defects in Synaptojanin1-deficient dopamine neurons despite lipid impairments. Furthermore, Synaptojanin1 and VPS35 exhibit correlated expression and dopamine-induced co-clustering in axons, supporting their broader roles in regulating synaptic surface proteins. Our work demonstrates a lipid-dependent endosomal mechanism that may contribute to motor deficits in early PD.

ID: 42387584
Title: SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.
Abstract: Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1G93A mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1G93A mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1G93A mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1G93A mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.

ID: 42391923
Title: VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.
Abstract: Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.

ID: 42417835
Title: Pharmacological mechanisms of fisetin in neurodegenerative disorders: regulation of neuroinflammatory, oxidative, and autophagic pathways.
Abstract: Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related progressive neurological conditions, are characterized by irreversible neuronal loss, cognitive impairment, and motor dysfunction. Accumulating evidence identifies chronic neuroinflammation as a critical contributor to disease initiation and progression. In particular, activation of the TLR-4/NF-κB signaling cascade in glial cells promotes excessive production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, together with induction of COX-2, iNOS, oxidative stress, and apoptosis, thereby exacerbating neuronal injury. Current pharmacotherapeutic strategies largely provide symptomatic benefit without effectively targeting the underlying pathogenic mechanisms. Fisetin, a naturally occurring flavonoid abundantly present in strawberries, apples, and persimmons, has recently attracted considerable attention owing to its pleiotropic neuroprotective properties. Experimental evidence indicates that fisetin suppresses TLR-4/NF-κB-mediated neuroinflammatory signaling, attenuates microglial activation, and enhances endogenous antioxidant defense through modulation of the Nrf2 pathway. Moreover, fisetin regulates apoptosis-associated mediators, thereby preserving neuronal integrity and survival. Notably, emerging studies demonstrate that fisetin-mediated inhibition of the TLR-4/Akt/mTOR signaling axis promotes autophagy-dependent α-syn clearance and neurogenesis, particularly in Parkinsonian models, highlighting its potential disease-modifying effects. These multifaceted pharmacological actions suggest that fisetin simultaneously targets interconnected inflammatory, oxidative, apoptotic, and proteostatic pathways implicated in neurodegeneration. Despite promising preclinical findings, additional investigations are required to elucidate its effects on inflammasome activation, glial cell crosstalk, pharmacokinetic behavior, and long-term clinical safety. Collectively, fisetin represents a promising multi-target therapeutic candidate for the management of inflammation-associated neurodegenerative disorders.

ID: 42418295
Title: Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
Abstract: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD. A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis. The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death. Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.

ID: 42419281
Title: Sealing and healing: A two-step model for plasma membrane repair.
Abstract: Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.

ID: 42427550
Title: Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.
Abstract: Lipid droplets (LDs) are conserved organelles that buffer lipid storage and stress, yet their dynamics and functions in neurons remain largely unknown. Here, we report activity-dependent dynamics of neuronal LDs, visualized by a novel, genetically encoded LD reporter (termed LipiDew), in both cultured neurons and mouse motor cortex. Using LipiDew, we found that various paradigms of neuronal activation induced predominant and transient formation of LDs in neurites. Disruption of autophagic LD degradation (lipophagy) resulted in abnormal lipid accumulation in dendritic spines and shafts, promoted recruitment of synaptic scaffolding proteins to LDs, and altered intracellular calcium kinetics in neurons. In addition, mice with neuron-specific genetic impairment of lipophagy showed motor function defects. Together, these findings identify activity-dependent LD formation and lipophagic clearance in neuronal compartments as a crucial regulatory mechanism of synaptic integrity and neuronal function.

ID: 42428500
Title: Mitochondrial-targeted actions of lycopene: evidence, mechanisms and future directions.
Abstract: Lycopene (LYC; C40H56), a dietary carotenoid, has emerged as a promising modulator of mitochondrial physiology across multiple cell types and animal models. Here we critically synthesize experimental evidence that LYC attenuates mitochondrial oxidative stress, preserves oxidative phosphorylation complex function and ATP production, reduces mitochondrial permeability transition and cytochrome-c-dependent apoptosis, and regulates mitochondrial quality-control pathways including mitophagy and (less consistently) biogenesis. Mechanistic readouts indicate activation of antioxidant axes (Nrf2/HO-1), modulation of SIRT1/SIRT3 and PGC-1 signaling, and downstream effects on Bcl-2 family proteins and caspase activation; targeted delivery systems (mitochondria-directed nanodots) further enhance mitochondrial targeting and functional rescue in neurodegeneration models. However, the literature shows substantial heterogeneity in experimental designs (dose, route, timing), mostly relies on injury/toxin paradigms, and frequently reports molecular changes without causal perturbation (genetic or pharmacologic) to establish mechanism. Importantly, data on mitochondrial dynamics (fusion/fission) remain sparse and mechanistic links between mitophagy, biogenesis and improved bioenergetics are often associative rather than causal. The objective of this review is to evaluate available evidence on how LYC modulates mitochondrial function, redox biology, biogenesis, dynamics, and autophagy (mitophagy), as well as mitochondria-dependent apoptosis, in animal and human cells, identify critical gaps, and propose experimental priorities to move the field toward translational studies. This work is concluded with concrete recommendations for mechanistic and translational research to validate LYC as a mitochondria-targeting agent.

ID: 42429504
Title: Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.
Abstract: The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.

ID: 42442908
Title: Role of ESCRT pathway and autophagy in neurodegenerative diseases.
Abstract: Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.

ID: 42450338
Title: Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
Abstract: Increasing evidence highlights a tight interplay between lipid metabolism and mitochondrial homeostasis in neurons, with disruptions in either pathway amplifying cellular vulnerability. PTEN-induced kinase 1 (PINK1), a familial Parkinson's disease (PD)-related gene and a key regulator of mitochondrial quality control and homeostasis, emerges at the intersections of lipid metabolic pathways, influencing membrane composition, fatty acid utilization, and neuronal energy balance. Within this review, we discuss the role of mitochondria as hubs for lipid metabolism, the mechanisms and functional consequences of neuronal lipid handling, and the complex bidirectional relationship between lipid dysregulation and PD pathology. Special focus is given to lipid-mitochondria crosstalk and how PINK1 orchestrates this interface to maintain neuronal homeostasis. Finally, we consider therapeutic perspectives that target lipid and mitochondrial pathways, highlighting strategies to restore cellular function and PD pathology.

ID: 42451086
Title: Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.
Abstract: Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.

ID: 42454195
Title: Stem cell extracellular vesicles for neuropsychiatric disorders and translation.
Abstract: Neuropsychiatric disorders represent a major global health challenge due to their high prevalence, chronic disability, and substantial socioeconomic burden. Although stem cell-based therapies offer regenerative potential, their clinical application is limited by poor post-transplantation survival, restricted targeted integration, and potential tumorigenicity. Stem cell-derived extracellular vesicles (SC-EVs), particularly exosomes, have emerged as a promising cell-free therapeutic approach. These vesicles can cross the blood-brain barrier (BBB) and exhibit high biocompatibility and low immunogenicity. This review summarizes the cellular origins and biogenesis of SC-EVs and evaluates current preclinical and clinical evidence supporting their therapeutic potential. Particular attention is given to acute ischemic stroke and progressive neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. In addition, the molecular mechanisms underlying their neuroprotective and regenerative effects are discussed, with a focus on modulating neuroinflammation, promoting neurogenesis, and enhancing synaptic plasticity. Finally, key advances and major challenges in the clinical translation of SC-EVs are outlined. Integrating current evidence, this review provides a framework and practical perspective for the continued development of SC-EV-based therapies for complex neurological disorders.

ID: 42460153
Title: Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization.
Abstract: Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals. We analysed 322,963 UK Biobank participants with bidirectional time-varying Cox models, one-year and two-year lag analyses, and competing-risk sensitivity models to quantify AD-PD clinical co-occurrence. We then analysed European-ancestry AD, PD and LBD GWAS summary statistics using linkage disequilibrium score regression (LDSC), GCTA-mtCOJO/GSMR, MAGMA, stratified LDSC, brain eQTL/mQTL SMR with HEIDI filtering, and Bayesian colocalization for selected methylation probes. Conditional loci were compared with original GWAS loci to separate shared liability from retained disorder-predominant associations. PD was associated with subsequent AD (fully adjusted HR 2.27, 95% CI 1.94-2.65; P = 6.40E-25), and AD was associated with subsequent PD (HR 3.14, 95% CI 2.56-3.85; P = 2.10E-28). Lag and competing-risk sensitivity analyses remained concordant. LDSC estimated positive genetic correlations for AD-PD (rg = 0.20; P = 0.0086) and PD-LBD (rg = 0.61; P = 0.0005). Conditioning reduced genome-wide significant loci from 14 to 9 for AD, from 24 to 21 for PD and from 5 to 2 for LBD. Retained loci included AD signals near CR1, BIN1, CLU, SPI1, MS4A, PICALM, ABCA7 and APOE; PD signals near GBA, NUCKS1, TMEM163, STK39, GAK/TMEM175, BST1, SNCA, LRRK2, MAPT and RIT2; and LBD signals near SNCA/MMRN1 and APOE. MAGMA and S-LDSC highlighted amyloid, lipid, immune, synaptic-vesicle and brain-tissue enrichment patterns. Brain QTL analyses prioritized retained eQTL and mQTL signals, and colocalization supported shared PD-GWAS/mQTL signals at HLA-DRB5, ARHGAP27, CRHR1, MAPT and KANSL1. AD and PD show bidirectional clinical co-occurrence, whereas conditional genetic analyses retain a smaller set of disease-predominant loci and regulatory signals across AD, PD and LBD. These findings refine cross-disorder interpretation and nominate loci for independent genetic and functional validation.

ID: 42463431
Title: VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.
Abstract: Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.

ID: 42463911
Title: Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.
Abstract: Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPRER). This UPRER activation remodels endoplasmic reticulum (ER) morphology and reprograms lipid metabolism, driving selective oleic acid (OA) accumulation. Crucially, this developmentally-installed OA reservoir confers lasting resilience against proteotoxic stress, an effect mimicked by OA supplementation. Together, these findings establish a chromatin-ER-lipid axis that developmentally primes adult proteostasis and suggest early-life interventions as a strategy to promote healthy aging and resilience to proteotoxic stress.

ID: 42464356
Title: Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.
Abstract: Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.

ID: 42465266
Title: Circulating extracellular vesicles in plasma carry accessible molecular signatures of aging in mice.
Abstract: Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimer's and Parkinson's disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.

ID: 42465339
Title: Dopamine Abundance Uncouples Neurodegeneration and Lifespan in a C. elegans Model of Parkinson's Disease.
Abstract: The neuropathology of Parkinson's disease is characterized by α-synuclein (α-syn) aggregation and dopaminergic (DAergic) neurodegeneration. While neuronal loss in C. elegans α-syn-induced neurodegeneration models is temporally age-dependent, prior research indicates it is uncoupled from the organismal aging process. Here we examined transgenic C. elegans expressing human A53T α-syn in DAergic neurons to determine the impact of localized DA metabolism on both neurodegeneration and organismal lifespan. Increasing endogenous DA levels through overexpression of tyrosine hydroxylase (CAT-2) exacerbated A53T-induced DAergic degeneration, whereas DA depletion via Δ cat-2 mutation rescued neuronal survival. By mutating a DA-interaction motif within α-syn, neurodegeneration was rendered insensitive to DA manipulation, thus confirming a structural basis for in vivo toxicity. We identified a DA-α-syn interaction that acts as a common upstream bridge whereby localized stress induces physiological responses in C. elegans . Genetically, this biochemical interaction acts as a pleiotropic trigger driving two compartmentalized responses: localized DAergic neurodegeneration via oxidative stress, and organism-wide, TFEB/ hlh-30 -dependent proteostatic remodeling that extends lifespan. Modulating autophagy, without exacerbating DA-mediated oxidative stress, represents a promising strategy to preserve adaptive systemic remodeling while limiting targeted neuronal damage.

ID: 42465421
Title: Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
Abstract: Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

ID: 42465724
Title: Implications of autolysosome- astrocyte-associated signature in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence and multi-omics and clinical validation.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and neurofibrillary tangles. Dysfunctional cellular clearance mechanisms, particularly autophagy-lysosomal pathways, and reactive astrocytosis are prominent pathological features, yet their interrelationship remains poorly defined. This study aimed to decipher a novel co-expression molecular signature linking autolysosomal dysfunction and astrocyte reactivity in AD pathogenesis. We performed Limma, WGCNA and Xcell algorithms in AD patient hippocampus bulk profiles for enrichment of astrocyte and autolysosome (AA)-associated DEGs. Next, explainable machine learning and consensus clustering enables the identification of AA-associated diagnostic model and molecular subgroups for AD patients at bulk level. Besides, AA-associated central pathogenic factor was identified, and its corresponding biological implications for AD were assessed at AD patient hippocampus single-cell level in temporal and spatial manners. Next deep learning algorithm (Drugreflector) and molecular docking enriched natural compounds for the treatment of AD by targeting AA-associated hub gene. Finally, AD clinical peripheral blood samples were collected for estimation of hub gene expression patterns. 5 AA-associated shared DEGs can elaborate diagnostic and patient stratification capacity for AD patients. HMGCR can be considered as astrocyte-distributed central pathogenic and Berberine-oriented therapeutic target for AD patients. Our findings unveil AA-associated diagnostic model and molecular subgroups coupled with HMGCR center pathogenic and druggable role in AD, which represents an actionable clinical target for AD patients.

ID: 42467143
Title: Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
Abstract: Neurodegenerative diseases are characterized by progressive neuronal loss driven by protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Among these, Parkinson's disease (PD) is a prevalent disorder marked by degeneration of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates. Emerging evidence indicates that mitochondrial dysfunction and metabolic dysregulation are central contributors to PD pathogenesis. Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, have emerged as key regulators of neuronal survival and metabolic homeostasis. Mechanistically, SIRT1 regulates α-synuclein aggregation, autophagy, and neuroinflammatory signaling, while SIRT3 preserves mitochondrial integrity and reduces oxidative stress. In contrast, SIRT2 has been implicated in microtubule destabilization and neurotoxicity, and its inhibition has demonstrated neuroprotective effects in experimental models. This review provides a comprehensive, up-to-date synthesis of the molecular mechanisms underlying sirtuin-mediated neuroprotection in PD and related neurodegenerative disorders. We further discuss the translational potential of targeting sirtuin pathways, including pharmacological modulators and NAD+-boosting strategies, while addressing current limitations and future directions for clinical translation.

ID: 42468901
Title: Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.
Abstract: Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.

ID: 42469943
Title: Mitochondria: the key hub for hematopoietic stem cell homeostasis maintenance and fate determination.
Abstract: Hematopoietic stem cells (HSCs) constitute the pivotal cellular subset sustaining long-term hematopoietic homeostasis, characterized by robust self‑renewal and multilineage differentiation potential. Under physiological conditions, HSCs undergo stepwise differentiation through rigorously controlled regulatory networks to produce a full repertoire of mature blood cells, fulfilling basal physiological demands. Upon exposure to stress or pathological insults (e.g., bone marrow niche dysregulation), HSCs rapidly activate emergency regenerative programs to reconstitute hematopoietic function and restore systemic homeostasis. As intracellular "powerhouses" and central hubs of metabolic regulation, mitochondria exert profound regulatory effects on HSCs fate determination. The dynamic balance of mitochondrial metabolism not only furnishes HSCs with sufficient bioenergy but also generates critical metabolic intermediates; meanwhile, the fine-tuning of oxidative stress and autophagic machinery ensures mitochondrial network integrity. These biological processes are intricately intertwined, forming a complex regulatory network that profoundly modulates HSCs self-renewal, lineage commitment, and long-term hematopoietic reconstitution potential. This review systematically dissects the multi-dimensional regulatory mechanisms by which mitochondria govern HSCs, elaborates on the synergistic interactions and antagonistic effects among distinct components of the regulatory circuitry, and defines the pivotal role of mitochondria in sustaining HSCs homeostasis and orchestrating their repair responses to cellular damage. This work establishes a novel theoretical framework for devising mitochondrial-targeted interventions to sustain metabolic homeostasis in HSCs. Furthermore, it lays a solid scientific foundation for the treatment of hematological diseases and the development of precision therapeutic strategies, offering new insights into the clinical management of hematopoietic disorders.

ID: 42471032
Title: Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.
Abstract: Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.

ID: 42471994
Title: Differential Proteomic Landscape of Plasma Neuron-Derived Extracellular Vesicles in Parkinson's Disease with and without RBD: A Pilot Investigation.
Abstract: Parkinson's disease (PD) is clinically heterogeneous, and the presence of rapid eye movement sleep behavior disorder (RBD) defines a distinct and aggressive subtype. There is an urgent need for molecular biomarkers to understand and identify these subtypes. Neuron-derived extracellular vesicles (nEVs) provide a window into brain pathology. In this pilot study, we isolated plasma nEVs via L1CAM immunocapture from 28 subjects (PD-RBD, PD-noRBD, and controls). Proteomic analysis was performed using data-independent acquisition mass spectrometry (DIA-MS). We quantified 1354 proteins. Comparative analysis revealed 239 differentially expressed proteins (DEPs) between PD-RBD and PD-noRBD. PD-RBD patients exhibited significantly higher levels of α-synuclein (SNCA) and showed pronounced enrichment in extracellular matrix remodeling (eg, NRGN, ELAV3) pathways. In contrast, PD-noRBD was characterized by dysregulated lipid metabolism (eg, APOE, CETP) and systemic inflammation. Specific DEPs correlated with motor severity, autonomic dysfunction, and brain iron deposition. This pilot study reveals distinct proteomic profiles between the plasma nEVs of PD-RBD and PD-noRBD, suggesting divergent pathophysiological processes involving structural/extracellular matrix remodeling versus systemic metabolic-inflammatory pathways. These findings provide a prioritized panel of candidate nEV biomarkers for subtype-specific stratification in PD, which warrant further large-scale clinical and functional validation.

ID: 42474555
Title: Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.
Abstract: Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.

ID: 42476121
Title: Global cellular responses to lysosomal damage.
Abstract: Lysosomes are membrane-bound organelles that orchestrate a wide range of cellular processes, including degradation, metabolism, signaling, gene regulation and quality control, while interacting with other organelles, thereby profoundly shaping cellular homeostasis and fate. Lysosomal membrane integrity is highly vulnerable to a broad spectrum of physiological and pathological insults, acting as both a cause and a consequence of diverse human conditions, including neurodegeneration, cancer, infectious disease and aging. Understanding the mechanisms by which cells respond to lysosomal damage is therefore of critical importance. Recent studies have revealed that cells deploy sophisticated damage response mechanisms locally to repair, remove, and replace damaged lysosomes. In contrast, how local lysosomal damage triggers global cellular responses is only beginning to be understood. This review summarizes recent conceptual advances in global cellular responses to lysosomal damage, encompassing translational, metabolic and transcriptional adaptations, and highlights their crucial roles in restoring cellular homeostasis and shaping outcomes in health and disease.

ID: 42476327
Title: Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
Abstract: Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.

ID: 42477717
Title: Amygdalar nuclei vulnerability to protein aggregates in Lewy body diseases.
Abstract: The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n = 6), Parkinson's disease (PD; n = 18), dementia with Lewy bodies (DLB; n = 9) and Alzheimer's disease with Lewy bodies (AD + LB; n = 15) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (Aβ; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to Aβ pathology varied per group but was highest in the PHA in AD + LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD + LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.

ID: 42480533
Title: Dual-function PROTAC suppresses ferroptosis and restores neuronal function via brain-targeted delivery.
Abstract: Targeted protein degradation (TPD) via proteolysis-targeting chimeras (PROTACs) offers a promising strategy for modulating disease-associated proteins, yet effective brain-preferred protein degradation remains challenging. Herein, we report a dual-function PROTAC, dACSL4, and its nose-to-brain delivery for brain-preferred protein degradation and therapeutic suppression of ferroptosis in neurodegeneration. dACSL4 selectively degrades acyl-CoA synthetase long-chain family member 4 (ACSL4) while concurrently activating peroxisome proliferator-activated receptor γ (PPARγ), thereby coordinating lipid metabolism and oxidative stress to suppress neuronal ferroptosis. dACSL4 achieved up to 30-fold greater protection against neuronal ferroptosis compared to conventional ferroptosis inhibitors. Intranasal delivery of dACSL4 using biodegradable lipid nanoparticles (BAmP-TK12) enabled brain-preferred ACSL4 degradation and PPARγ activation, reducing lipid peroxidation and preserving dopaminergic neurons in a Parkinson's disease model, ultimately improving motor function. Our findings establish a modular strategy for brain-preferred protein degradation and highlight the therapeutic potential of dual-function degraders for ferroptosis suppression in neurodegenerative diseases.

ID: 42481480
Title: Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.
Abstract: Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer's disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.

ID: 42483155
Title: Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.
Abstract: Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.

ID: 42483593
Title: Circular RNA circDNAJC5 Regulates Ultrafine Particle-Disrupted Microglial Lipid Metabolism via the Sphingolipid Signaling Pathway.
Abstract: Ultrafine particles (PM0.1) can penetrate the brain and disrupt microglial function. Dysregulated lipid metabolism in activated microglia contributes to the development of Alzheimer's disease (AD), yet the epigenetic mechanisms underlying PM0.1-induced lipid metabolic disruption remain poorly understood. Circular RNAs (circRNAs) are emerging regulators of lipid metabolism, prompting us to investigate their role in PM0.1-exposed microglia. In vitro models of PM0.1-treated microglia (HMC3 and BV2) were established. We identified circDNAJC5, a lipid metabolism-associated circRNA, as significantly downregulated during PM0.1-induced lipid metabolic disruption. circDNAJC5 silencing aggravated lipid dysregulation, whereas its overexpression mitigated PM0.1-induced metabolic alterations. circDNAJC5 functioned as a molecular sponge for miR-98-5p, thereby regulating sphingomyelin synthase 1 (SMS1), a key enzyme in the sphingolipid signaling pathway. circDNAJC5 downregulation and lipid metabolic abnormalities were further validated in the brains of PM-exposed mice and AD mouse models, as well as in the blood of elderly individuals with cognitive impairment and hyperlipidemia. These findings highlight an epigenetic mechanism linking environmental exposure to microglial lipid metabolism and suggest circDNAJC5 as a potential biomarker for neurodegenerative and metabolic disorders.

ID: 42488639
Title: Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.
Abstract: Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8+ T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4+ T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.

ID: 42491938
Title: Dynamic, state-dependent characteristics of cognitive fluctuations in Lewy body dementia: a magnetoencephalography study.
Abstract: Cognitive fluctuations are a hallmark clinical feature of Lewy body dementia (LBD), yet their underlying neural mechanisms remain poorly understood. This study aimed to identify dynamic, state-dependent neural signatures of cognitive fluctuations in LBD using magnetoencephalography and dynamic functional connectivity based on hidden Markov modelling. Resting-state magnetoencephalography data were acquired from individuals with LBD, Parkinson's disease without dementia and cognitively normal controls. Hidden Markov modelling was used to identify transient brain states followed by spectral analyses across regions and states. Additionally, associations between regional spectral power and cognitive fluctuations severity, measured by the Clinician Assessment of Fluctuation, were assessed. Patients with LBD exhibited a distinct pattern of brain dynamics, particularly in two states (States 2 and 6), characterized by increased fractional occupancy of State 2 and markedly reduced occupancy of State 6, contrasting with the more distributed state engagement observed in Parkinson's disease and normal controls. Spectral analyses revealed widespread slowing in LBD, with elevated theta/beta power ratios in frontal, parietal and visual cortices-most pronounced in States 2 and 6. Region-specific theta/beta power ratio elevations were identified in the anterior cingulate, medial prefrontal cortex, posterior cingulate, dorsal visual stream and auditory cortex. Critically, Clinician Assessment of Fluctuation scores correlated positively with spectral power in low frequency (δ and θ) and negatively with power in the high frequency (α and β), particularly in the ventral visual stream, default mode network hubs and sensorimotor regions. These findings reveal dynamic and spatially specific electrophysiological abnormalities in LBD closely linked to cognitive fluctuations severity, suggesting that magnetoencephalography-hidden-Markov-model characteristics hold promise as biomarkers for diagnosis, monitoring and therapeutic targeting in LBD.