In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impair...Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impairment in individuals with AD.However,the underlying mechanisms remains poorly understood.This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD.Methods APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu(BL 23)and Baihui(GV 20).Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus(DRN).Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests.Golgi staining,western blot,and immunostaining were utilized to determine EA-induced neuroprotection.Results EA at Shenshu(BL 23)and Baihui(GV 20)effectively ameliorated learning and memory impairments in APP/PS1 mice.EA attenuated dendritic spine loss,increased the expression levels of PSD95,synaptophysin,and brain-derived neurotrophic factor in hippocampus.Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B.Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory.Conclusion EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN.Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.展开更多
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金supported by grants from the Shenzhen Science and Technology Program(No.2021-22154)National Natural Science Foundation of China(No.82205271,No.82374564,and No.82074566)+1 种基金Wuhan Medical Research Project(No.WZ21Q09)Key Chinese Medicine Project of Hubei Provincial Natural Science Foundation(No.2023AFD112).
文摘Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impairment in individuals with AD.However,the underlying mechanisms remains poorly understood.This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD.Methods APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu(BL 23)and Baihui(GV 20).Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus(DRN).Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests.Golgi staining,western blot,and immunostaining were utilized to determine EA-induced neuroprotection.Results EA at Shenshu(BL 23)and Baihui(GV 20)effectively ameliorated learning and memory impairments in APP/PS1 mice.EA attenuated dendritic spine loss,increased the expression levels of PSD95,synaptophysin,and brain-derived neurotrophic factor in hippocampus.Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B.Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory.Conclusion EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN.Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.
