Molecular Neurodegeneration最新文献

{"title":"Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.","authors":"Mariana I Muñoz-García,Yuetiva Deming,Ferran Lugo-Hernández,Sterling Johnson,Sanjay Asthana,Gwendlyn Kollmorgen,Clara Quijano-Rubio,Cynthia Carlsson,Ozioma C Okonkwo,David Pérez-Martinez,Alberto Villarejo-Galende,Kaj Blennow,Marc Suárez-Calvet,Henrik Zetterberg,Barbara B Bendlin,Estrella Morenas-Rodríguez","doi":"10.1186/s13024-025-00901-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00901-5","url":null,"abstract":"BACKGROUNDSynaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.METHODSWe analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, α-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) and the Alzheimer's and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for Aβ42 and p-tau. Subgroup analyses were performed based on AT classification, APOE-ε4 status, and median splits of Aβ42/Aβ40 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.RESULTSWe found significant cross-sectional associations between sTREM2 and α-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and α-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03, respectively). In ALFA+, lower baseline α-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with Aβ42/Aβ40 ratio above the median (β = -0.01, p = 0.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (β = -0.01, p = 0.03 for WRAP, β = -0.01, p = 0.04 in ALFA+).CONCLUSIONSSynaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"356 1","pages":"109"},"PeriodicalIF":15.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305696","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":"Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies","authors":"Emily L. Ward, Larry Benowitz, Thomas M. Brunner, Guojun Bu, Michel Cayouette, Valeria Canto‐Soler, Sandro Dá Mesquita, Adriana Di Polo, Aaron DiAntonio, Xin Duan, Jeffrey L. Goldberg, Zhigang He, Yang Hu, Shane A. Liddelow, Anna La Torre, Milica Margeta, Francisco Quintana, Karthik Shekhar, Beth Stevens, Sally Temple, Humsa Venkatesh, Derek Welsbie, John G. Flanagan","doi":"10.1186/s13024-025-00858-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00858-5","url":null,"abstract":"Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting “Solving Neurodegeneration,” (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 “Solving Neurodegeneration 2” meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283439","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":"Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.","authors":"Livia La Barbera,Paraskevi Krashia,Gilda Loffredo,Emma Cauzzi,Maria Luisa De Paolis,Martina Montanari,Luana Saba,Elena Spoleti,Serena Ficchì,Claudio Zaccone,Marco De Bardi,Claudia Palazzo,Ramona Marino,Emanuele Claudio Latagliata,Stefano Puglisi-Allegra,Giovanna Borsellino,Flavio Keller,Luisa Lo Iacono,Maria Teresa Viscomi,Annalisa Nobili,Marcello D'Amelio","doi":"10.1186/s13024-025-00893-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00893-2","url":null,"abstract":"BACKGROUNDSmaller midbrain volumes predict Alzheimer's Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia. Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.METHODSUsing adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.RESULTSThe concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.CONCLUSIONSThese results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance toward","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":"105"},"PeriodicalIF":15.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277159","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":"Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer’s disease genetic pathways","authors":"Bjørn-Eivind Kirsebom, Johanna Nilsson, Ellen Vromen, Peter Mikael Arnesen, Atle Bjørnerud, Ann Brinkmalm, Geir Bråthen, Gøril Rolfseng Grøntvedt, Jonas Jarholm, Kaja Nordengen, Lene Pålhaugen, Per Selnes, Nikias Siafarikas, Ragnhild Eide Skogseth, Sandra Tecelão, Knut Waterloo, Panpan You, Henrik Zetterberg, Dag Aarsland, Betty Tijms, Pieter Jelle Visser, Kaj Blennow, Tormod Fladby","doi":"10.1186/s13024-025-00899-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00899-w","url":null,"abstract":"Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277422","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":"Correction: Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein","authors":"Jingfeng Liang, Rongzhen Li, Garry Wong, Xiaobing Huang","doi":"10.1186/s13024-025-00902-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00902-4","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction to: Molecular Neurodegeneration (2025) 20:90&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s13024-025-00879-0&lt;/b&gt;&lt;/p&gt;&lt;p&gt;The original article has been updated to correct the framing of Figs. 1 and 2, as well as to restore the legend of Fig. 2 which was mistakenly incorporated into the main body text.&lt;/p&gt;&lt;span&gt;Author notes&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Jingfeng Liang and Rongzhen Li have contributed equally to this work.&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;h3&gt;Authors and Affiliations&lt;/h3&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;College of Pharmacy, Shenzhen Technology University, Shenzhen, 518000, China&lt;/p&gt;&lt;p&gt;Jingfeng Liang &amp; Xiaobing Huang&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Neurology, Baiyun District People’s Hospital of Guangzhou, Guangzhou, 510000, China&lt;/p&gt;&lt;p&gt;Jingfeng Liang&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Global Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau S.A.R, 999078, China&lt;/p&gt;&lt;p&gt;Rongzhen Li &amp; Garry Wong&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;span&gt;Authors&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;span&gt;Jingfeng Liang&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Rongzhen Li&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Garry Wong&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Xiaobing Huang&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;h3&gt;Corresponding author&lt;/h3&gt;&lt;p&gt;Correspondence to Xiaobing Huang.&lt;/p&gt;&lt;h3&gt;Publisher’s note&lt;/h3&gt;&lt;p&gt;Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Open Access&lt;/b&gt; This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.&lt;/p&gt;\u0000&lt;p&gt;Reprints and permissions&lt;/p&gt;&lt;img alt=\"Check for updates. Verify currency and authenticity via CrossMark\" height=\"81\" loading=\"lazy\" src=\"data:image/svg+xml;base64,PHN2ZyBoZ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"69 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255688","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":"Brain somatic mutations in Alzheimer’s disease: linking genetic mosaicism to neurodegeneration","authors":"Zuguang Li, Juan Zhang, Zhiqiang Liu, Lu Yu, Chunqing Yang, Luoman Zhang, Zhigao Xiang, Feng Hu, Nadezda Brazh, Kai Shu, Ling-Qiang Zhu, Dan Liu","doi":"10.1186/s13024-025-00895-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00895-0","url":null,"abstract":"Somatic mutations are DNA sequence changes that occur in non-reproductive cells during an organism’s life and are not inherited by offspring. Growing evidence implicates somatic mutations in Alzheimer’s disease (AD), linking them to both disease onset and progression. Recent advancements in single-cell sequencing and genome-wide analyses have revealed higher mutation burdens in neurons, particularly in AD-related genes such as Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and amyloid precursor protein (APP). These mutations, which include single nucleotide variants (SNVs), small insertions and deletions (Indels), structural variations (SVs) and mitochondrial DNA (mtDNA) mutations may disrupt neuronal function and synaptic connectivity. However, some somatic mutations may also serve a neuroprotective role. The underlying mechanisms remain incompletely understood. This review explores the emerging role of somatic mutations in AD, highlighting their links to disease progression. It also underscores the potential for future research to uncover new therapeutic targets by integrating advanced sequencing technologies and gene-editing approaches, which may enable more precise interventions to correct somatic mutations and slow disease progression.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"59 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246424","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":"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}