TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer’s disease  

作　　者：Jia Lu Kexin Wu Xudong Sha Jiayuan Lin Hongzhuan Chen Zhihua Yu 

机构地区：[1]Department of Pharmacology and Chemical Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

出　　处：《Translational Neurodegeneration》2024年第1期300-323,共24页转化神经变性病(英文)

基　　金：supported by grants from the National Natural Science Foundation of China(82173791);Science and Technology Commission of Shanghai Municipality(23ZR1436600).

摘　　要：Background Persistent innate and adaptive immune responses in the brain contribute to the progression of Alzhei-mer’s disease(AD).APOE4,the most important genetic risk factor for sporadic AD,encodes apolipoprotein E4,which by itself is a potent modulator of immune response.However,little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems.Transient receptor potential vanilloid type 1(TRPV1)channel is a ligand-gated,nonselective cation channel with Ca^(2+)permeability,which has been proposed as a neuroprotective target in AD.Methods Using Ca^(2+)-sensitive dyes,dynamic changes of Ca^(2+)in microglia were measured,including exogenous Ca^(2+)uptake and endoplasmic reticulum Ca^(2+)release.The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux.Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with micro-glia-specific TRPV1 gene deficiency.Results Both APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopa-thy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts.Further,cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia,subsequently accompanied by T cell infiltration.In addition,TRPV1-mediated transient Ca^(2+)influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2,promoted autophagic activity and reduced lysosomal cholesterol accumulation,which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model.Moreover,microglia-specific deficiency of TRPV1 gene accelerated glial inflammation,T cell response and assoc

关 键 词：APOE4 CHOLESTEROL TRPV1 MICROGLIA Tau 

分 类 号：R74[医药卫生—神经病学与精神病学]