Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreas...Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.展开更多
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(82122023 and U22A20294).
文摘Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
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.