Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring ...Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring antibodies against Bim(NAbs-Bim)exist in human blood,with their levels and functions unknown in AD.In this study,we found that circulating NAbs-Bim were decreased in AD patients.Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions.Furthermore,NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβdeposition,tau hyperphosphorylation,microgliosis,and neuronal apoptosis in APP/PS1 mice.In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein.These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.展开更多
基金supported by the National Natural Science Foundation of China(81930028,81971024,and 81971033).
文摘Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring antibodies against Bim(NAbs-Bim)exist in human blood,with their levels and functions unknown in AD.In this study,we found that circulating NAbs-Bim were decreased in AD patients.Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions.Furthermore,NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβdeposition,tau hyperphosphorylation,microgliosis,and neuronal apoptosis in APP/PS1 mice.In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein.These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.
