Molecular Neurodegeneration最新文献

{"title":"The transcription factor combination MEF2 and KLF7 promotes axonal sprouting in the injured spinal cord with functional improvement and regeneration-associated gene expression","authors":"Callan L. Attwell, Inés Maldonado-Lasunción, Ruben Eggers, Bastiaan A. Bijleveld, Ward M. Ellenbroek, Natascha Siersema, Lotte Razenberg, Dédé Lamme, Nitish D. Fagoe, Ronald E. van Kesteren, August B. Smit, Joost Verhaagen, Matthew R. J. Mason","doi":"10.1186/s13024-025-00805-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00805-4","url":null,"abstract":"Axon regeneration after injury to the central nervous system (CNS) is limited by an inhibitory environment but also because injured neurons fail to initiate expression of regeneration associated genes (RAGs). The potential of strong RAG expression to promote regeneration in the CNS is exemplified by the conditioning lesion model, whereby peripheral nerve injury promotes regeneration of centrally projecting branches of the injured neurons. RAG expression could potentially be induced by delivery of the right set of transcription factors (TFs). We here aim to identify TF combinations that activate this program. We first analysed binding site motifs in promoters of the RAG program to identify nine candidate growth-promoting TFs. These were systematically screened in vitro to identify combinations that had potent neurite-growth promoting activity. Next, adeno-associated viral vectors were used to express these TF combinations in vivo in L4/L5 dorsal root ganglia to test whether they would promote regeneration in a spinal cord injury model (dorsal column lesion) in female rats. To determine whether they could activate the RAG program we carried out gene expression profiling on laser-dissected dorsal root ganglion neurons specifically expressing these TF combinations, and of DRG neurons that had been axotomized. Promoter analysis identified ATF3, Jun, CEBPD, KLF7, MEF2, SMAD1, SOX11, STAT3 and SRF as candidate RAG-activating TFs. In vitro screening identified two TF combinations, KLF7/MEF2 and ATF3/KLF7/MEF2, that had potent neurite-growth promoting activity, the latter being the more powerful. In vivo, KLF7/MEF2, but not ATF3/KLF7/MEF2 or KLF7 or MEF2 alone, promoted axonal sprouting into the dorsal column lesion site and led to improved functional recovery. Gene expression profiling revealed that unexpectedly, the MEF2-VP16 construct used had little transcriptional activity in vivo, suggesting additional steps may be required to achieve full MEF2 activity. All combinations except MEF2 alone induced RAG expression mirroring that induced by axotomy to significant extents, while ATF3/KLF7/MEF2, KLF7 and ATF3, but not KLF7/MEF2 also induced apoptosis-related genes which may hinder regeneration. The TF combination KLF7/MEF2 partially mimics the conditioning lesion effect, inducing axonal sprouting into a dorsal column lesion and driving significant RAG expression, and also promotes functional improvement.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"29 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367450","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":"Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice","authors":"Ali Yousefian-Jazi, Suhyun Kim, Jiyeon Chu, Seung-Hye Choi, Phuong Thi Thanh Nguyen, Uiyeol Park, Min-gyeong Kim, Hongik Hwang, Kyungeun Lee, Yeyun Kim, Seung Jae Hyeon, Hyewhon Rhim, Hannah L. Ryu, Grewo Lim, Thor D. Stein, Kayeong Lim, Hoon Ryu, Junghee Lee","doi":"10.1186/s13024-024-00792-y","DOIUrl":"https://doi.org/10.1186/s13024-024-00792-y","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis. Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"9 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367453","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":"Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic behavioral variant frontotemporal degeneration","authors":"Ting Shen, Jacob W. Vogel, Vivianna M. Van Deerlin, EunRan Suh, Laynie Dratch, Jeffrey S. Phillips, Lauren Massimo, Edward B. Lee, David J. Irwin, Corey T. McMillan","doi":"10.1186/s13024-025-00806-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00806-3","url":null,"abstract":"Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72 repeat expansions or pathogenic variants in GRN or MAPT. Functional enrichment analyses were conducted on each gene list significantly associated with cortical thickness. Additionally, we mapped neurotransmitter receptor/transporter density maps to the cortical thickness maps, to uncover different correlation patterns for each genetic form. Furthermore, we examined whether the identified genes were enriched for pathology-related genes by using previously identified genes linked to TDP-43 positive neurons and genes associated with tau pathology. For each genetic form of bvFTD, we identified cortical thickness signatures and gene sets associated with them. The cortical thickness associated genes for GRN-bvFTD were significantly involved in neurotransmitter system and circadian entrainment. The different patterns of spatial correlations between synaptic density and cortical thinning, further confirmed the critical role of neurotransmission and synaptic signaling in shaping brain structure, especially in the GRN-bvFTD group. Furthermore, we observed significant overlap between genes linked to TDP-43 pathology and the gene sets associated with cortical thickness in C9orf72-bvFTD and GRN-bvFTD but not the MAPT-bvFTD group providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD also shared genes displaying consistent directionality, with those exhibiting either positive or negative correlations with cortical thickness in C9orf72-bvFTD showing the same direction (positive or negative) in GRN-bvFTD. MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures compared to the other two genetic forms. The genes that exhibited significantly positive or negative correlations with cortical thickness in MAPT-bvFTD showed opposing directionality in C9orf72-bvFTD and GRN-bvFTD. Overall, this integrative transcriptomic approach identified several new shared and disparate genes associated with regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression. These findings illuminated the intricate molecular underpinnings contributing to the heterogeneous nature of disease distribution in bvFTD with distinct genetic backgrounds.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367449","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":"Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD","authors":"Shaowei Wang, Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Lu Qian, Julia TCW, Helena C. Chui, Dante Dikeman, Isaac Asante, Stan G. Louie, David A. Bennett, Zoe Arvanitakis, Alan T. Remaley, Bilal E. Kerman, Hussein N. Yassine","doi":"10.1186/s13024-025-00802-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00802-7","url":null,"abstract":"Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear. We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways. Transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses. Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"77 2 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083437","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":"Lewy body diseases and the gut","authors":"Timothy R. Sampson, Malú Gámez Tansey, Andrew B. West, Rodger A. Liddle","doi":"10.1186/s13024-025-00804-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00804-5","url":null,"abstract":"Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"30 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056322","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 and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases","authors":"Francisco J. Garcia, Myriam Heiman","doi":"10.1186/s13024-025-00799-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00799-z","url":null,"abstract":"Many diseases and disorders of the nervous system suffer from a lack of adequate therapeutics to halt or slow disease progression, and to this day, no cure exists for any of the fatal neurodegenerative diseases. In part this is due to the incredible diversity of cell types that comprise the brain, knowledge gaps in understanding basic mechanisms of disease, as well as a lack of reliable strategies for delivering new therapeutic modalities to affected areas. With the advent of single cell genomics, it is now possible to interrogate the molecular characteristics of diverse cell populations and their alterations in diseased states. More recently, much attention has been devoted to cell populations that have historically been difficult to profile with bulk single cell technologies. In particular, cell types that comprise the cerebrovasculature have become increasingly better characterized in normal and neurodegenerative disease contexts. In this review, we describe the current understanding of cerebrovasculature structure, function, and cell type diversity and its role in the mechanisms underlying various neurodegenerative diseases. We focus on human and mouse cerebrovasculature studies and discuss both origins and consequences of cerebrovascular dysfunction, emphasizing known cell type-specific vulnerabilities in neuronal and cerebrovascular cell populations. Lastly, we highlight how novel insights into cerebrovascular biology have impacted the development of modern therapeutic approaches and discuss outstanding questions in the field.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"3 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054941","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":"Cell-specific transcriptional signatures of vascular cells in Alzheimer’s disease: perspectives, pathways, and therapeutic directions","authors":"Soumilee Chaudhuri, Minyoung Cho, Julia C. Stumpff, Paula J. Bice, Özkan İş, Nilüfer Ertekin-Taner, Andrew J. Saykin, Kwangsik Nho","doi":"10.1186/s13024-025-00798-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00798-0","url":null,"abstract":"Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is marked by profound neurovascular dysfunction and significant cell-specific alterations in the brain vasculature. Recent advances in high throughput single-cell transcriptomics technology have enabled the study of the human brain vasculature at an unprecedented depth. Additionally, the understudied niche of cerebrovascular cells, such as endothelial and mural cells, and their subtypes have been scrutinized for understanding cellular and transcriptional heterogeneity in AD. Here, we provide an overview of rich transcriptional signatures derived from recent single-cell and single-nucleus transcriptomic studies of human brain vascular cells and their implications for targeted therapy for AD. We conducted an in-depth literature search using Medline and Covidence to identify pertinent AD studies that utilized single-cell technologies in human post-mortem brain tissue by focusing on understanding the transcriptional differences in cerebrovascular cell types and subtypes in AD and cognitively normal older adults. We also discuss impaired cellular crosstalk between vascular cells and neuroglial units, as well as astrocytes in AD. Additionally, we contextualize the findings from single-cell studies of distinct endothelial cells, smooth muscle cells, fibroblasts, and pericytes in the human AD brain and highlight pathways for potential therapeutic interventions as a concerted multi-omic effort with spatial transcriptomics technology, neuroimaging, and neuropathology. Overall, we provide a detailed account of the vascular cell-specific transcriptional signatures in AD and their crucial cellular crosstalk with the neuroglial unit. Endothelial and mural cell types mediate dysregulated transcriptional pathways and cell-cell interactions in AD. The neurovascular unit (NVU) is composed of various cell types, including endothelial cells, mural cells (pericytes, smooth muscle cells), fibroblast neurons, microglia, and astrocytes. Dysregulated transcriptional pathways in AD involve multiple pathways, notably immune responses, and angiogenesis common to both endothelial and mural cells. Additionally, pathways involving neuroinflammation and amyloid clearance are prominent in endothelial cell types, while mural cells exhibit pathways related to growth factors, cytoskeletal remodeling and synaptic function. In addition, crosstalk within the NVU and gliovascular unit (GVU) is altered in AD, with altered cell-cell communication evident, with increased interactions between endothelial cells, pericytes, neurons, and microglia, and decreased interactions between endothelial cells, fibroblasts, astrocytes, and neurons. Figure created with BioRender.com. Abbreviations: AD, Alzheimer's disease; NVU, Neurovascular unit; CNS, Central Nervous System. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"37 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054950","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":"Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications","authors":"Sijia He, Ziying Xu, Xianlin Han","doi":"10.1186/s13024-025-00803-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00803-6","url":null,"abstract":"Alzheimer’s disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049668","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":"Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions","authors":"Grace Kuo, Ramhari Kumbhar, William Blair, Valina L. Dawson, Ted M. Dawson, Xiaobo Mao","doi":"10.1186/s13024-025-00797-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00797-1","url":null,"abstract":"α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020555","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 Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology","authors":"Kristine M. Tran, Nellie E. Kwang, Claire A. Butler, Angela Gomez-Arboledas, Shimako Kawauchi, Cassandra Mar, Donna Chao, Rocio A. Barahona, Celia Da Cunha, Kate I. Tsourmas, Zechuan Shi, Shuling Wang, Sherilyn Collins, Amber Walker, Kai-Xuan Shi, Joshua A. Alcantara, Jonathan Neumann, Duc M. Duong, Nicholas T. Seyfried, Andrea J. Tenner, Frank M. LaFerla, Lindsay A. Hohsfield, Vivek Swarup, Grant R. MacGregor, Kim N. Green","doi":"10.1186/s13024-024-00793-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00793-x","url":null,"abstract":"Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau. In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice. These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"74 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992784","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}