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 Tau is an intracellular protein that plays a crucial role in stabilizing microtubules.However,it can aggregate into various forms under pathological conditions and be secreted into the brain parenchyma.Whil...Background Tau is an intracellular protein that plays a crucial role in stabilizing microtubules.However,it can aggregate into various forms under pathological conditions and be secreted into the brain parenchyma.While the consequences of tau aggregation within neurons have been extensively studied,the effects of extracellular paired helical filaments of tau(ePHF-tau)on neurons and astrocytes are still poorly understood.Methods This study examined the effect of human ePHF-tau(2N4R)on primary cultures of rat neuroglia,focusing on changes in neurites or synapses by microscopy and analysis of synaptosome and mitochondria proteomic profiles after treatment.In addition,we monitored the behavior of mitochondria in neurons and astrocytes separately over three days using high-speed imaging and high-throughput acquisition and analysis.Results ePHF-tau was efficiently cleared by astrocytes within two days in a 3D neuron-astrocyte co-culture model.Treatment with ePHF-tau led to a rapid increase in synaptic vesicle production and active zones,suggesting a potential excitotoxic response.Proteomic analyses of synaptosomal and mitochondrial fractions revealed distinct mitochondrial stress adaptations:astrocytes exhibited elevated mitochondrial biogenesis and turnover,whereas neuronal mitochondria displayed only minor oxidative modifications.In a mixed culture model,overexpression of tau 1N4R specifically in astrocytes triggered a marked increase in mitochondrial biogenesis,coinciding with enhanced synaptic vesicle formation in dendrites.Similarly,astrocyte-specific overexpression of PGC1alpha produced a comparable pattern of synaptic vesicle production,indicating that astrocytic mitochondrial adaptation to ePHF-tau may significantly influence synaptic function.Conclusions These findings suggest that the accumulation of PHF-tau within astrocytes drives changes in mitochondrial biogenesis,which may influence synaptic regulation.This astrocyte-mediated adaptation to tauopathy highlights the potential role of astrocytes in modulating synaptic dynamics in response to tau stress,opening avenues for therapeutic strategies aimed at astrocytic mechanisms in the context of neurodegenerative diseases.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funding provided by University of Lausanne.The Synapsis Foundation,Novartis Foundation,MCM fondation and AC Immune supported this work.
文摘Background Tau is an intracellular protein that plays a crucial role in stabilizing microtubules.However,it can aggregate into various forms under pathological conditions and be secreted into the brain parenchyma.While the consequences of tau aggregation within neurons have been extensively studied,the effects of extracellular paired helical filaments of tau(ePHF-tau)on neurons and astrocytes are still poorly understood.Methods This study examined the effect of human ePHF-tau(2N4R)on primary cultures of rat neuroglia,focusing on changes in neurites or synapses by microscopy and analysis of synaptosome and mitochondria proteomic profiles after treatment.In addition,we monitored the behavior of mitochondria in neurons and astrocytes separately over three days using high-speed imaging and high-throughput acquisition and analysis.Results ePHF-tau was efficiently cleared by astrocytes within two days in a 3D neuron-astrocyte co-culture model.Treatment with ePHF-tau led to a rapid increase in synaptic vesicle production and active zones,suggesting a potential excitotoxic response.Proteomic analyses of synaptosomal and mitochondrial fractions revealed distinct mitochondrial stress adaptations:astrocytes exhibited elevated mitochondrial biogenesis and turnover,whereas neuronal mitochondria displayed only minor oxidative modifications.In a mixed culture model,overexpression of tau 1N4R specifically in astrocytes triggered a marked increase in mitochondrial biogenesis,coinciding with enhanced synaptic vesicle formation in dendrites.Similarly,astrocyte-specific overexpression of PGC1alpha produced a comparable pattern of synaptic vesicle production,indicating that astrocytic mitochondrial adaptation to ePHF-tau may significantly influence synaptic function.Conclusions These findings suggest that the accumulation of PHF-tau within astrocytes drives changes in mitochondrial biogenesis,which may influence synaptic regulation.This astrocyte-mediated adaptation to tauopathy highlights the potential role of astrocytes in modulating synaptic dynamics in response to tau stress,opening avenues for therapeutic strategies aimed at astrocytic mechanisms in the context of neurodegenerative diseases.
