beta(2)-Microglobulin coaggregates with A beta and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice

作者全名："Zhao, Yini; Zheng, Qiuyang; Hong, Yujuan; Gao, Yue; Hu, Jiaojiao; Lang, Maoju; Zhang, Hongfeng; Zhou, Ying; Luo, Hong; Zhang, Xian; Sun, Hao; Yan, Xiao-Xin; Huang, Timothy Y. Y.; Wang, Yan-Jiang; Xu, Huaxi; Liu, Cong; Wang, Xin"

作者地址："[Zhao, Yini; Zheng, Qiuyang; Hong, Yujuan; Gao, Yue; Lang, Maoju; Zhang, Hongfeng; Luo, Hong; Zhang, Xian; Sun, Hao; Wang, Xin] Xiamen Univ, Inst Neurosci, State Key Lab Cellular Stress Biol, Fujian Prov Key Lab Neurodegenerat Dis & Aging Res, Xiamen, Peoples R China; [Zhao, Yini; Zheng, Qiuyang; Zhang, Hongfeng; Wang, Xin] Xiamen Univ, Shenzhen Res Inst, Shenzhen, Peoples R China; [Hu, Jiaojiao; Liu, Cong] Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai, Peoples R China; [Zhou, Ying] Xiamen Univ, Natl Inst Data Sci Hlth & Med, Sch Med, Xiamen, Peoples R China; [Yan, Xiao-Xin] Cent South Univ, Xiangya Med Sch, Dept Anat & Neurobiol, Changsha, Peoples R China; [Huang, Timothy Y. Y.] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, La Jolla, CA USA; [Wang, Yan-Jiang] Third Mil Med Univ, Daping Hosp, Dept Neurol, Chongqing, Peoples R China; [Wang, Yan-Jiang] Third Mil Med Univ, Daping Hosp, Ctr Clin Neurosci, Chongqing, Peoples R China; [Xu, Huaxi] Xiamen Univ, Affiliated Hosp 1, Ctr Brain Sci, Fujian Prov Key Lab Neurodegenerat Dis & Aging Res, Xiamen, Peoples R China; [Xu, Huaxi] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing, Peoples R China"

通信作者："Wang, X (通讯作者)，Xiamen Univ, Inst Neurosci, State Key Lab Cellular Stress Biol, Fujian Prov Key Lab Neurodegenerat Dis & Aging Res, Xiamen, Peoples R China.; Wang, X (通讯作者)，Xiamen Univ, Shenzhen Res Inst, Shenzhen, Peoples R China."

来源：NATURE NEUROSCIENCE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000999556200001

JCR分区：Q1

影响因子：21.2

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Zhao et al. identified beta(2)-microglobulin (beta M-2) as an essential factor driving beta-amyloid (A beta) neurotoxicity and cognitive impairment in mouse models of Alzheimer's disease (AD) and implicated targeting beta M-2-A beta coaggregation as a strategy for AD therapeutics. Extensive studies indicate that beta-amyloid (A beta) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that A beta itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of beta(2)-microglobulin (beta M-2) and A beta that trigger neurodegeneration in AD. beta M-2, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of beta M-2 aggravates amyloid pathology independent of MHC class I, and coaggregation with beta M-2 is essential for A beta neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated beta M-2 depletion mitigates AD-associated neuropathology, and inhibition of beta M-2-A beta coaggregation with a beta M-2-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify beta M-2 as an essential factor for A beta neurotoxicity and a potential target for treating AD."

基金机构："National Natural Science Foundation of China [U21A20358, 81822014, 31871077, 81701349, 81802823, 2021YFA1101401, 2021ZD0202400]; National Key R&D Program of China [82271451, 81701130]; Natural Science Foundation of Fujian Province of China [2021J02004, 2017J06021, 2018J01054]; Guangdong Basic and Applied Basic Research Foundation [2021B1515120081]; Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects [2021ZD0201103, 2021ZD0201803]; Fundamental Research Funds for the Chinese Central Universities [20720220052]"

基金资助正文："We thank G. Fu, Y. Shen, C. Xiao and N. Xiao for sharing experimental resources. We thank Y. Zhao, L. Zhong, L. Yao, C. Wu, Q. Liu, X. You, J. Huang, B. Xie, Q. Deng, T. Guo, H. Zhang, S. Zhang and X. Sheng for technical assistance. This work was supported by National Natural Science Foundation of China (U21A20358, 81822014 and 31871077 to X.W.), the National Key R & D Program of China (2021YFA1101401 and STI2030-Major Projects-2021ZD0202400 to X.W.), National Natural Science Foundation of China (82271451 and 81701130 to Q.Z.; 81701349 to H.Z.; 81802823 to Y. Zhou), Natural Science Foundation of Fujian Province of China (2021J02004 and 2017J06021 to X.W.; 2018J01054 to Y. Zhou), Guangdong Basic and Applied Basic Research Foundation (2021B1515120081 to X.W.), Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects (2021ZD0201103 and 2021ZD0201803 to X.-X.Y.) and Fundamental Research Funds for the Chinese Central Universities (20720220052 to Q.Z.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript."