<p><b>Correction to: Molecular Neurodegeneration (2025) 20:90</b></p><p><b>https://doi.org/10.1186/s13024-025-00879-0</b></p><p>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.</p><span>Author notes</span><ol><li><p>Jingfeng Liang and Rongzhen Li have contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>College of Pharmacy, Shenzhen Technology University, Shenzhen, 518000, China</p><p>Jingfeng Liang & Xiaobing Huang</p></li><li><p>Department of Neurology, Baiyun District People’s Hospital of Guangzhou, Guangzhou, 510000, China</p><p>Jingfeng Liang</p></li><li><p>Department of Global Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau S.A.R, 999078, China</p><p>Rongzhen Li & Garry Wong</p></li></ol><span>Authors</span><ol><li><span>Jingfeng Liang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rongzhen Li</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Garry Wong</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaobing Huang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Xiaobing Huang.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> 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.</p> <p>Reprints and permissions</p><img alt="Check for updates. Verify currency and authenticity via CrossMark" height="81" loading="lazy" src="data:image/svg+xml;base64,PHN2ZyBoZ
{"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":"<p><b>Correction to: Molecular Neurodegeneration (2025) 20:90</b></p><p><b>https://doi.org/10.1186/s13024-025-00879-0</b></p><p>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.</p><span>Author notes</span><ol><li><p>Jingfeng Liang and Rongzhen Li have contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>College of Pharmacy, Shenzhen Technology University, Shenzhen, 518000, China</p><p>Jingfeng Liang & Xiaobing Huang</p></li><li><p>Department of Neurology, Baiyun District People’s Hospital of Guangzhou, Guangzhou, 510000, China</p><p>Jingfeng Liang</p></li><li><p>Department of Global Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau S.A.R, 999078, China</p><p>Rongzhen Li & Garry Wong</p></li></ol><span>Authors</span><ol><li><span>Jingfeng Liang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rongzhen Li</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Garry Wong</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaobing Huang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Xiaobing Huang.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> 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.</p>\u0000<p>Reprints and permissions</p><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}
Pub Date : 2025-10-09DOI: 10.1186/s13024-025-00895-0
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
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.
{"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}
Pub Date : 2025-10-01DOI: 10.1186/s13024-025-00892-3
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
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.
{"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}
Pub Date : 2025-09-29DOI: 10.1186/s13024-025-00898-x
Lauren K. Wareham, David J. Calkins
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.
{"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}
Pub Date : 2025-09-29DOI: 10.1186/s13024-025-00897-y
Yi Zhou, Christopher K. Glass
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.
{"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}
Pub Date : 2025-09-26DOI: 10.1186/s13024-025-00877-2
Christopher Daniel Morrone, Arielle A. Tsang, W. Haung Yu
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
{"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}
Pub Date : 2025-09-26DOI: 10.1186/s13024-025-00891-4
Doris Chen, Stella Wigglesworth-Littlewood, Frank J. Gunn-Moore
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.
{"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}
Pub Date : 2025-09-26DOI: 10.1186/s13024-025-00889-y
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
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.
帕金森病（PD）影响着全世界数百万人，但只有5-10%的患者患有孟德尔遗传的单基因形式的疾病。编码α -突触核蛋白（aSyn）的基因SNCA是第一个与家族性帕金森病相关的基因，从那时起，该基因的一些错义变异和增殖已被确定为常染色体显性帕金森病的罕见病因。在这项研究中，我们报告了一种新的SNCA突变在患者的鉴定，该患者表现为复杂的神经生成障碍，并有非常规的神经病理结果。我们还进行了深入的分子研究的影响，新的aSyn突变。本文对1例新型aSyn错义突变患者及其家庭成员进行了研究。我们提出临床特征，基因检测-全外显子组测序（WES）和神经病理结果。使用生化、生物物理和细胞分析广泛研究了这种aSyn变异的功能后果。患者表现出复杂的神经退行性疾病，包括全身性肌阵挛、运动迟缓、左臂肌张力障碍和失用症。WES鉴定出一种新的杂合SNCA变异（cDNA 40G > a; protein G14R）。神经病理检查显示广泛的非典型aSyn病理，伴有额颞叶变性（FTLD）型分布和神经变性模式，伴丰富的环状神经元包涵体和少量少突胶质包涵体。Sanger测序在患者的一位86岁的健康父母中证实了SNCA变异，表明不完全外显。核磁共振研究表明，G14R突变诱导了aSyn的局部结构改变，并在体外纤化实验中降低了硫黄素T的结合。有趣的是，G14R aSyn纤维在低温电子显微镜下显示出与路易体不同的纤维形态。G14R变异体的细胞研究显示，包涵体形成增加，膜结合增强，丝氨酸- 129磷酸化的动态可逆性受损。观察到的非典型神经病理特征与G51D aSyn变体相似，表明SNCA变体具有独特的临床和病理表型，这进一步得到了突变型aSyn的特性的支持。
{"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}
Pub Date : 2025-09-02DOI: 10.1186/s13024-025-00888-z
Kamil Borkowski, Nuanyi Liang, Na Zhao, Matthias Arnold, Kevin Huynh, Naama Karu, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Takahisa Kanekiyo, Guojun Bu, Rima Kaddurah-Daouk
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.
{"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}
Pub Date : 2025-08-29DOI: 10.1186/s13024-025-00883-4
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
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.
{"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}
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