Background Alzheimer’s disease(AD)is characterized by accumulation of amyloid-β(Aβ)plaques,tau neurofibrillary Tangles and synaptic dysfunction.The aim of this study was to map the distributions of synaptic vesicle...Background Alzheimer’s disease(AD)is characterized by accumulation of amyloid-β(Aβ)plaques,tau neurofibrillary Tangles and synaptic dysfunction.The aim of this study was to map the distributions of synaptic vesicle protein 2A(SV2A)and other synaptic proteins in the brain and the brain-derived extracellular vesicles(BDEVs)of AD patients,analyze their associations with Aβ,tau,and the apolipoprotein E(APOE)ε4 allele,and investigate the biological role of SV2A.Methods Mass spectrometry-based proteomics of BDEVs and immunohistochemistry staining were conducted on postmortem brain samples from 57 AD patients and 48 nondemented controls.The levels of SV2A,synaptophysin(SYP),and other synaptic proteins in the brain tissues and the BDEVs,and their associations with Aβ,tau(phospho-tau and Braak stages),other proteins and the APOEε4 allele,were analyzed.Results SV2A levels were significantly lower in AD patients than in nondemented controls,particularly in the hippocampus and entorhinal cortex.APOEε4 carriers presented further reductions in SV2A levels compared with noncarriers.The SV2A levels in BDEVs and brain tissues were positively correlated with SYP levels and negatively correlated with Aβand phospho-tau levels.Reductions in SV2A were associated with decreased levels of other synaptic proteins,such as synaptotagmins,GAP43,and SNAP25.SV2A emerged as a central hub with interactions with proteins from subnetworks related to synaptic vesicle formation and fusion.Conclusion SV2A levels in brain tissues and BDEVs are reduced in AD patients,particularly in those carrying the APOEε4 allele,and are correlated with Aβand tau pathologies.SV2A may serve as a valuable biomarker for monitoring synaptic dysfunction and progression in AD.展开更多
Background Alzheimer’s disease(AD)is the most prominent form of dementia worldwide.It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner.This has led to the prion-like propag...Background Alzheimer’s disease(AD)is the most prominent form of dementia worldwide.It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner.This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell.Human brain-derived extracellular vesicles(BD-EVs)isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading.Knowing the rich diversity of EVs,isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.Methods Here,enriched-small EVs(eSEVs)and enriched-large EVs(eLEVs)were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs’integrity.Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.Results BD-EVs were stratified according to their size(eSEVs and eLEVs)and characterized to define new markers specific to EVs in AD.Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature.Notably,AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling,while AD eLEVs proteins were more related to respiratory electron transport and brain immunity.Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.Conclusion This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.展开更多
基金the Swiss Center for Advanced Human Toxicology(SCAHT-AP_22_01)DR and RN received funding from the Swiss National Science Foundation(31ND30_213444)+1 种基金KR received funding from the Centre Hospitalier Universitaire Vaudois(CHUV)LB and MC are supported by LiCEND(Lille Centre of Excellence in Neurodegenerative Disorders).
文摘Background Alzheimer’s disease(AD)is characterized by accumulation of amyloid-β(Aβ)plaques,tau neurofibrillary Tangles and synaptic dysfunction.The aim of this study was to map the distributions of synaptic vesicle protein 2A(SV2A)and other synaptic proteins in the brain and the brain-derived extracellular vesicles(BDEVs)of AD patients,analyze their associations with Aβ,tau,and the apolipoprotein E(APOE)ε4 allele,and investigate the biological role of SV2A.Methods Mass spectrometry-based proteomics of BDEVs and immunohistochemistry staining were conducted on postmortem brain samples from 57 AD patients and 48 nondemented controls.The levels of SV2A,synaptophysin(SYP),and other synaptic proteins in the brain tissues and the BDEVs,and their associations with Aβ,tau(phospho-tau and Braak stages),other proteins and the APOEε4 allele,were analyzed.Results SV2A levels were significantly lower in AD patients than in nondemented controls,particularly in the hippocampus and entorhinal cortex.APOEε4 carriers presented further reductions in SV2A levels compared with noncarriers.The SV2A levels in BDEVs and brain tissues were positively correlated with SYP levels and negatively correlated with Aβand phospho-tau levels.Reductions in SV2A were associated with decreased levels of other synaptic proteins,such as synaptotagmins,GAP43,and SNAP25.SV2A emerged as a central hub with interactions with proteins from subnetworks related to synaptic vesicle formation and fusion.Conclusion SV2A levels in brain tissues and BDEVs are reduced in AD patients,particularly in those carrying the APOEε4 allele,and are correlated with Aβand tau pathologies.SV2A may serve as a valuable biomarker for monitoring synaptic dysfunction and progression in AD.
基金supported by grants from the program Investissement d’Avenir LabEx(investing in the future laboratory excellence)DISTALZ(Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease)+2 种基金France Alzheimer,Fondation pour la Recherche Medicale and ANR grants(TONIC,TauSeed)Our laboratories are also supported by LiCEND(Lille Centre of Excellence in Neurodegenerative Disorders)CNRS,Inserm,Metropole Europeenne de Lille,University of Lille,I-SITE ULNE,Region Hauts de France and FEDER.The OrganOmics platform of PRISM Inserm U1192 which is recognized and supported by the University of Lille and,the Infrastructure PROFI(https://www.profi prote omics.fr/)and the GIS IbiSA(https://www.ibisa.net/).The OrganOmics platform(Villeneuve d’Ascq,France)is also supported by Region Hauts de France and FEDER funding.
文摘Background Alzheimer’s disease(AD)is the most prominent form of dementia worldwide.It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner.This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell.Human brain-derived extracellular vesicles(BD-EVs)isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading.Knowing the rich diversity of EVs,isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.Methods Here,enriched-small EVs(eSEVs)and enriched-large EVs(eLEVs)were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs’integrity.Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.Results BD-EVs were stratified according to their size(eSEVs and eLEVs)and characterized to define new markers specific to EVs in AD.Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature.Notably,AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling,while AD eLEVs proteins were more related to respiratory electron transport and brain immunity.Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.Conclusion This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.
