Disease-Associated Neurotoxic Astrocyte Markers in Alzheimer Disease Based on Integrative Single-Nucleus RNA Sequencing

作者全名:"Yu, Wuhan; Li, Yin; Zhong, Fuxin; Deng, Zhangjing; Wu, Jiani; Yu, Weihua; Lue, Yang"

作者地址:"[Yu, Wuhan; Zhong, Fuxin; Deng, Zhangjing; Wu, Jiani; Lue, Yang] Chongqing Med Univ, Dept Geriatr, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Li, Yin] Fudan Univ, Dept Thorac Surg, Zhongshan Hosp, Shanghai 200032, Peoples R China; [Yu, Weihua] Chongqing Med Univ, Inst Neurosci, Chongqing 400016, Peoples R China"

通信作者:"Lue, Y (通讯作者),Chongqing Med Univ, Dept Geriatr, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."












关键词:Alzheimer disease; Biomarkers; Neurotoxic astrocytes; Bulk RNA-seq; snRNA-seq

摘要:"Alzheimer disease (AD) is an irreversible neurodegenerative disease, and astrocytes play a key role in its onset and progression. The aim of this study is to analyze the characteristics of neurotoxic astrocytes and identify novel molecular targets for slowing down the progression of AD. Single-nucleus RNA sequencing (snRNA-seq) data were analyzed from various AD cohorts comprising about 210,654 cells from 53 brain tissue. By integrating snRNA-seq data with bulk RNA-seq data, crucial astrocyte types and genes associated with the prognosis of patients with AD were identified. The expression of neurotoxic astrocyte markers was validated using 5 x FAD and wild-type (WT) mouse models, combined with experiments such as western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence. A group of neurotoxic astrocytes closely related to AD pathology was identified, which were involved in inflammatory responses and pathways related to neuron survival. Combining snRNA and bulk tissue data, ZEP36L, AEBP1, WWTR1, PHYHD1, DST and RASL12 were identified as toxic astrocyte markers closely related to disease severity, significantly elevated in brain tissues of 5 x FAD mice and primary astrocytes treated with A beta. Among them, WWTR1 was significantly increased in astrocytes of 5 x FAD mice, driving astrocyte inflammatory responses, and has been identified as an important marker of neurotoxic astrocytes. snRNA-seq analysis reveals the biological functions of neurotoxic astrocytes. Six genes related to AD pathology were identified and validated, among which WWTR1 may be a novel marker of neurotoxic astrocytes."

基金机构:Chongqing Talent Plan

基金资助正文:No Statement Available