b2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function

作者全名："Gao, Yue; Hong, Yujuan; Huang, Lihong; Zheng, Shuang; Zhang, Haibin; Wang, Shihua; Yao, Yi; Zhao, Yini; Zhu, Lin; Xu, Qiang; Chai, Xuhui; Zeng, Yuanyuan; Zeng, Yuzhe; Zheng, Liangkai; Zhou, Yulin; Luo, Hong; Zhang, Xian; Zhang, Hongfeng; Zhou, Ying; Fu, Guo; Sun, Hao; Huang, Timothy Y.; Zheng, Qiuyang; Xu, Huaxi; Wang, Xin"

作者地址："[Gao, Yue; Hong, Yujuan; Huang, Lihong; Zheng, Shuang; Zhang, Haibin; Wang, Shihua; Zhu, Lin; Xu, Qiang; Chai, Xuhui; Zeng, Yuzhe; Luo, Hong; Zhang, Xian; Zhang, Hongfeng; Sun, Hao; Zheng, Qiuyang; Wang, Xin] Xiamen Univ, Affiliated Hosp 1, Inst Neurosci,Sch Med, Fac Med & Life Sci,Fujian Prov Key Lab Neurodegene, Xiamen 361005, Fujian, Peoples R China; [Gao, Yue; Zhang, Hongfeng; Zheng, Qiuyang; Wang, Xin] Shenzhen Res Inst Xiamen Univ, Shenzhen 518057, Guangdong, Peoples R China; [Yao, Yi] Fujian Med Univ, Xiamen Humanity Hosp, Dept Funct Neurosurg, Xiamen 361003, Fujian, Peoples R China; [Zeng, Yuanyuan; Zhou, Ying] Xiamen Univ, Natl Inst Data Sci Hlth & Med, Sch Med, Xiamen 361102, Fujian, Peoples R China; [Zheng, Liangkai; Zhou, Yulin] Xiamen Univ, Women & Childrens Hosp, United Diagnost & Res Ctr Clin Genet, Sch Med, Xiamen 361103, Peoples R China; [Fu, Guo] Xiamen Univ, Canc Res Ctr, Sch Med, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China; [Huang, Timothy Y.] Sanford Burnham Prebys Med Discovery Inst, Neurosci Initiat, La Jolla, CA 92037 USA; [Xu, Huaxi] Xiamen Univ, Affiliated Hosp 1, Inst Neurosci, Ctr Brain Sci ,Sch Med, Xiamen 361005, Fujian, Peoples R China; [Xu, Huaxi] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Wang, X (通讯作者)，Xiamen Univ, Affiliated Hosp 1, Inst Neurosci,Sch Med, Fac Med & Life Sci,Fujian Prov Key Lab Neurodegene, Xiamen 361005, Fujian, Peoples R China.; Wang, X (通讯作者)，Shenzhen Res Inst Xiamen Univ, Shenzhen 518057, Guangdong, Peoples R China."

来源：CELL

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000953139200001

JCR分区：Q1

影响因子：64.5

年份：2023

卷号：186

期号：5

开始页：1026

结束页：+

文献类型：Article

关键词：　

摘要："Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of b2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunc-tion in DS and related cognitive disorders."

基金机构："National Key R&D Program of China [2021YFA1101401, STI2030-Major Projects-2021ZD0202400]; National Natural Science Foundation of China [U21A20358, 81822014, 31871077, 82271451, 81701130, 81701349, 81802823]; Natural Science Foundation of Fujian Province of China [2021J02004, 2017J06021, 2018J01054]; Guangdong Basic and Applied Basic Research Foundation [2021B1515120081]; Fundamental Research Funds for the Chinese Central Universities [20720220052]"

基金资助正文："We thank Jianyuan Sun, Shujia Zhu, Jiahuai Han, Sheng-Cai Lin and Wei Lu for helpful discussion. We also thank Jiahuai Han, Changchun Xiao, Nengming Xiao and Kejia Wang for sharing experimental mice, Yonghao Zhao, Zhiping Zeng, Aidong Han, Yixin Chen, Wenxin Luo, Changchuan Xie, Qingfeng Liu, Baoying Xie, Suqin Wu, Lishan Zhang, Qianwen Huang, Shuo Zhang, Ting Yao, Huan Hou and Yaya Zheng for technical assistance. This work was supported by the National Key R & D Program of China (2021YFA1101401 and STI2030-Major Projects-2021ZD0202400 to X.W.) , the National Natural Science Foundation of China (U21A20358, 81822014, and 31871077 to X.W.; 82271451 and 81701130 to Q.Z.; 81701349 to Hongfeng Zhang; 81802823 to Ying Zhou), the Natural Science Foundation of Fujian Province of China (2021J02004 and 2017J06021 to X.W.; 2018J01054 to Y.Z.) , and Guangdong Basic and Applied Basic Research Foundation (2021B1515120081 to X.W.) , and the Fundamental Research Funds for the Chinese Central Universities (20720220052 to Q.Z.) ."