Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be...Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβclearance in AD.In the current study,flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin(PSK)on AD-related pathology in vitro and in vivo.We found that PSK,widely used in therapy for various cancers,has the potential to enhance Aβuptake and intracellular processing by human monocytes in vitro.After administration of PSK by intraperitoneal injection,APP/PS1 mice performed better in behavioral tests,along with reduced Aβdeposition,neuroinflammation,neuronal loss,and tau hyperphosphorylation.These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβclearance by blood monocytes and alleviating AD-like pathology.展开更多
The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in ...The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in 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
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
基金the National Natural Science Foundation of China(81930028,91749206,81625007,and 31921003).
文摘Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβclearance in AD.In the current study,flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin(PSK)on AD-related pathology in vitro and in vivo.We found that PSK,widely used in therapy for various cancers,has the potential to enhance Aβuptake and intracellular processing by human monocytes in vitro.After administration of PSK by intraperitoneal injection,APP/PS1 mice performed better in behavioral tests,along with reduced Aβdeposition,neuroinflammation,neuronal loss,and tau hyperphosphorylation.These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβclearance by blood monocytes and alleviating AD-like pathology.
基金supported by the National Natural Science Foundation of China(81870860).
文摘The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in 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.
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.
