Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice  

作　　者：Yanli Zhang Tian Li Jie Miao Zhina Zhang Mingxuan Yang Zhuoran Wang Bo Yang Jiawei Zhang Haiting Li Qiang Su Junhong Guo 

机构地区：[1]Department of Neurology,First Hospital of Shanxi Medical University,Taiyuan,Shanxi Province,China [2]Department of Neurology,Sixth Hospital of Shanxi Medical University(General Hospital of Tisco),Taiyuan,Shanxi Province,China [3]Department of Physiology,Key Laboratory of Cellular Physiology,Ministry of Education,Shanxi Medical University,Taiyuan,Shanxi Province,China [4]Department of Hernia and Abdominal Wall Surgery,Shanxi Bethune Hospital,Shanxi Academy of Medical Sciences,Tongji Shanxi Hospital,Third Hospital of Shanxi Medical University,Taiyuan,Shanxi Province,China [5]Department of Laboratory Medicine of Fenyang College,Shanxi Medical University,Fenyang,Shanxi Province,China

出　　处：《Neural Regeneration Research》2025年第2期533-547,共15页中国神经再生研究（英文版）

基　　金：supported by STI2030-Major Projects,No.2021ZD 0201801(to JG);Shanxi Province Basic Research Program,No.20210302123429(to QS).

摘　　要：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.

关 键 词：Alzheimer’s disease amyloid-β APP/PS1 mice cerebrovascular endothelial cells cognitive deficits gamma-glutamyl transferase 5 neurovascular unit nuclear factor‐kappa B synaptic plasticity β-site APP cleaving enzyme 1 

分 类 号：R749.16[医药卫生—神经病学与精神病学]