Molecular Neurodegeneration最新文献

{"title":"Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease","authors":"Isabel Castanho, Pourya Naderi Yeganeh, Carles A. Boix, Sarah L. Morgan, Hansruedi Mathys, Dmitry Prokopenko, Bartholomew White, Larisa M. Soto, Giulia Pegoraro, Saloni Shah, Athanasios Ploumakis, Nikolas Kalavros, David A. Bennett, Christoph Lange, Doo Yeon Kim, Lars Bertram, Li-Huei Tsai, Manolis Kellis, Rudolph E. Tanzi, Winston Hide","doi":"10.1186/s13024-025-00892-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00892-3","url":null,"abstract":"A significant proportion of individuals maintain cognition despite extensive Alzheimer’s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Making tracks: microglia and the extracellular matrix","authors":"Lauren K. Wareham, David J. Calkins","doi":"10.1186/s13024-025-00898-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00898-x","url":null,"abstract":"Microglia are resident immune cells of the central nervous system (CNS) and critical regulators of neural homeostasis, mediating immune surveillance, synaptic remodeling, debris clearance, and inflammatory signaling. Emerging evidence highlights the extracellular matrix (ECM) as important to microglial behavior in both physiological and pathological contexts. The CNS ECM is a dynamic and bioactive scaffold composed of three primary compartments: interstitial matrix, basement membranes at neurovascular and neuroepithelial interfaces, and perineuronal nets (PNNs). Each compartment exhibits distinct molecular architectures, ranging from fibrillar collagens and glycoproteins in basement membranes to chondroitin sulfate proteoglycans and hyaluronan-rich structures in PNNs. In this review we examine how microglia engage with and reshape the ECM to dynamically respond to disruptions in homeostasis with aging and disease. We discuss the concept of the microglial–ECM “interactome”, which may represent a molecular interface through which microglia sense, modify, and respond to their extracellular environment. This interactome enables microglia to enact fine-scale ECM remodeling during routine surveillance, as well as large-scale alterations under pathological conditions to help preserve function and motility. In aging and disease, dysregulation of the microglial-ECM interactome is characterized by aberrant mechanotransduction, elevated proteinase activity, remodeling of the ECM, and sustained pro-inflammatory cytokine release. These pathological changes compromise ECM integrity, challenge microglial activity, and contribute to progressive neurovascular and synaptic dysfunction. Deciphering the molecular mechanisms underpinning microglial–ECM interactions is essential for understanding region-specific vulnerability in neurodegeneration and may reveal new therapeutic targets for preserving ECM structure and countering CNS disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia networks within the tapestry of alzheimer’s disease through spatial transcriptomics","authors":"Yi Zhou, Christopher K. Glass","doi":"10.1186/s13024-025-00897-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00897-y","url":null,"abstract":"Understanding Alzheimer’s disease (AD) at the cellular level requires insights into how diverse cell types respond to hallmark pathologies, including amyloid plaques and tau aggregates. Although single-cell transcriptomic approaches have illuminated the trajectories of AD progression in both animal models and human brains, they often lack the spatial context necessary to fully comprehend cell–cell interactions and microenvironmental influences. In this review, we discuss recent advances in spatial transcriptomics—integrating both imaging- and sequencing-based methods—that map gene expression within intact brain tissues. We highlight how these technologies have revealed regional heterogeneity and functional diversity among microglia, and their dynamic interactions with astrocytes, neurons, and oligodendrocytes in both aging and AD. Emphasis is placed on the interactions of microglia within the amyloid plaque niche, their contribution to synaptic degeneration, and how aging accelerates microglial and glial activation. By synthesizing findings from AD mouse models and physiologically characterized human tissues, we provide a comprehensive view of the cellular interplay driving AD pathogenesis and offer insights into potential therapeutic avenues.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"155 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagic impairment in sleep–wake circuitry is linked to sleep loss at the early stages of Alzheimer’s disease","authors":"Christopher Daniel Morrone, Arielle A. Tsang, W. Haung Yu","doi":"10.1186/s13024-025-00877-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00877-2","url":null,"abstract":"Proteostasis, in particular the impairment of autophagic activity, is linked to sleep dysregulation and is an early sign of dementias including Alzheimer’s disease (AD). This coupling of events may be a critical alteration driving proteinopathy and AD progression. In the present study, we investigated sleep–wake and memory regulating neurons for vulnerability to autophagic impediment, and related these findings to progression of the sleep and cognitive phenotype. Using the double knock-in AD mouse model, AppNL−G−FxMAPT, we examined phenotypic and pathological alterations at several timepoints and compared to age-matched single knock-in MAPT mice. Spatial learning, memory and executive Function were investigated in the Barnes maze. Sleep was investigated by 24-h locomotor activity and EEG. Immunostaining for autophagic, neuronal and pathological markers was conducted in brain regions related to memory (hippocampus, prefrontal cortex, entorhinal cortex) and the sleep–wake cycle (hypothalamus, locus coeruleus). Hippocampal electrophysiological recordings were conducted to probe neuronal Function during object investigation. A 3-day sleep disruption was conducted in MAPT mice to investigate autophagic changes following sleep loss. Autophagy was activated in MAPT mice with trehalose to probe effects on sleep recovery. We identified that disrupted sleep occurred from early-stages in AppNL−G−FxMAPT mice, that sleep declined over age, and sleep deficits preceded cognitive impairments in late-stages. Cytoplasmic autophagic impediment in hypothalamic and locus coeruleus sleep–wake neurons occurred in early-stage AppNL−G−FxMAPT mice, prior to significant β-amyloid deposition in these regions, with a failure of lysosomal flux over disease progression. Autophagic changes in the hippocampus and cortex at early-stage were predominantly in processes and less frequently associated with the lysosome. Plaque-associated autophagic and lysosomal accumulations were frequent from the early-stage. Sex differences in the AD phenotype were prominent, including greater cognitive decline in males than females, linked to increased proteostasis burden in EC layer II neurons and hippocampal tau in the late-stage. Conversely, sleep impairments were more rapid in females including less REM sleep recovery than males, along with greater autophagic burden in hippocampal processes of female AppNL−G−FxMAPT mice. We probed the sleep-cognition linkage demonstrating hippocampal electrophysiological slowing during cognitive processing in mid-stage AppNL−G−FxMAPT mice, prior to cognitive decline. We provide evidence for a positive feedback loop in the autophagic-sleep relationship by demonstrating that disrupted sleep in MAPT mice led to arrhythmic sleep patterns and accumulations of autophagic aggregates in the hippocampus and hypothalamus, similar to as was seen in the early Alzheimer’s phenotype. We further probed the autophagy-sleep linkage by treating MAPT mice with trehalose to acti","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"52 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Hippo signaling pathway as a therapeutic target in Alzheimer’s disease","authors":"Doris Chen, Stella Wigglesworth-Littlewood, Frank J. Gunn-Moore","doi":"10.1186/s13024-025-00891-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00891-4","url":null,"abstract":"The Hippo signaling pathway is well-known for its regulation of organ size, cell proliferation, apoptosis, and cell migration and differentiation. Recent studies have demonstrated that Hippo signaling also plays important roles in the nervous system, being involved in neuroinflammation, neuronal differentiation, and neuronal death and degeneration. As such, dysregulation of Hippo signaling, particularly of its core kinases MST1/2 and LATS1/2, has begun to attract attention in the Alzheimer’s disease (AD) field. Here, we discuss the therapeutic potential of targeting the Hippo pathway in AD by providing an overview of Hippo signaling with regards to its function in the nervous system, evidence for its dysregulation in AD patients and models, and recent studies involving genetic or pharmacological modulation of this pathway in AD. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"94 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features","authors":"Christof Brücke, Mohammed Al-Azzani, Nagendran Ramalingam, Maria Ramón, Rita L. Sousa, Fiamma Buratti, Michael Zech, Kevin Sicking, Leslie Amaral, Ellen Gelpi, Aswathy Chandran, Aishwarya Agarwal, Susana R. Chaves, Claudio O. Fernández, Ulf Dettmer, Janin Lautenschläger, Markus Zweckstetter, Ruben Fernandez Busnadiego, Alexander Zimprich, Tiago Fleming Outeiro","doi":"10.1186/s13024-025-00889-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00889-y","url":null,"abstract":"Parkinson’s disease (PD) affects millions of people worldwide, but only 5–10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation. A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing—whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine‐129 phosphorylation. The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"73 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE genotype influences on the brain metabolome of aging mice – role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype","authors":"Kamil Borkowski, Nuanyi Liang, Na Zhao, Matthias Arnold, Kevin Huynh, Naama Karu, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Takahisa Kanekiyo, Guojun Bu, Rima Kaddurah-Daouk","doi":"10.1186/s13024-025-00888-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00888-z","url":null,"abstract":"Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"60 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity","authors":"Brandon B. Holmes, Thaddeus K. Weigel, Jesseca M. Chung, Sarah K. Kaufman, Brandon I. Apresa, James R. Byrnes, Kaan S. Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V. L. Rose, Yun Zhang, Alissa L. Nana, Dina Alter, Lea T. Grinberg, Salvatore Spina, Kevin K. Leung, Bruce L. Miller, Carlo Condello, Martin Kampmann, William W. Seeley, Jaeda C. Coutinho-Budd, James A. Wells","doi":"10.1186/s13024-025-00883-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00883-4","url":null,"abstract":"To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"82 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology","authors":"Denise Balta, Anish Varghese, Susy Prieto Huarcaya, Alessandro Di Spiezio, André R. A. Marques, Enes Yağız Akdaş, Doğa Tabakacilar, Alice Drobny, Christian Werner, Wei Xiang, Rebecca Mächtel, Jan Philipp Dobert, Anna Fejtova, Franziska Richter, Melanie Küspert, Philipp Arnold, Paul Saftig, Friederike Zunke","doi":"10.1186/s13024-025-00886-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00886-1","url":null,"abstract":"The autophagy-lysosomal pathway is crucial for maintaining homeostasis and survival of neurons, hence defects in this system have been associated with neurodegeneration, including Parkinson's disease (PD). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related proteins such as amyloid- $$:{upbeta:}$$ , huntingtin and the prion protein. While there are studies implicating CTSB and CTSL as mediators of α-synuclein/SNCA clearance, their exact roles remain unclear. We previously demonstrated that recombinant procathepsin D can enhance the clearance of pathological-aggregates of SNCA both in vitro and in vivo, as well as restoring autophagy function. These results prompted us to investigate the role of the two cysteine proteases CTSB and CTSL regarding SNCA degradation by dosing recombinant human procathepsin B (rHsCTSB) and procathepsin L (rHsCTSL) alone or in combination. We here demonstrate that both proteases are efficiently endocytosed by neuronal cells and transported to lysosomes, where they undergo maturation into active enzymes. Treatment with either rHsCTSB or rHsCTSL resulted in a reduction of different SNCA species, present in Triton-insoluble protein fractions as well as sensitive for various pathology- and structure-specific antibodies analyzed via Western blot, immunofluorescence and ELISA. These effects were found to be similar in all models used here: dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the SNCA A53T mutation, ex vivo organotypic brain slices and primary neuronal cultures of human SNCA overexpressing Thy1 mice. Interestingly, our data so far do not indicate a synergistic effect of both cysteine cathepsins when applied together. As proof-of-concept for future therapeutic studies, intracranial injections of both recombinant enzymes reduced SNCA in brains of a transgenic mouse model (Ctsd knockout) harboring SNCA pathology. Moreover, treatment with recombinant CTSB and CTSL improved lysosomal/autophagy functions indicated by recovery of β-glucocerebrosidase (GCase) activity and SQSTM1 (p62) level. Further, SNCA-dependent synaptic defects as well as toxicity was reduced after treatment of neuronal cells. These findings suggest that enhancing lysosomal CTSB or CTSL effectively degrades pathology-associated SNCA, suggesting a potential therapeutic protease-based strategy for PD and other synucleinopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"23 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model","authors":"Hai-Shan Jiao, Yi-Jun Ge, Liang-Yu Huang, Ying Liu, Bang-Sheng Wu, Piao-Piao Lian, Yi-Ning Hao, Shan-Shan Han, Yi-Ting Li, Kai-Min Wu, Chen-Yun Wu, Tian-Lin Cheng, Peng Yuan, Jin-Tai Yu","doi":"10.1186/s13024-025-00887-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00887-0","url":null,"abstract":"Alzheimer’s disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}