β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function

• Published in: Cell 2023-03, Vol.186 (5), p.1026-1038.e20
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; beta 2-Microglobulin - metabolism; beta 2-Microglobulin - pharmacology; Cognitive Dysfunction - metabolism; Cross Reactions; Down Syndrome - blood; Down Syndrome - metabolism; Humans; Mice; Parabiosis; Proteomics; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2023.01.021

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 β2-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 dysfunction in DS and related cognitive disorders. [Display omitted] •Elevation of plasma B2M levels impairs cognitive and synaptic function•Peripheral depletion of B2M ameliorates synaptic deficits in DS mice•B2M antagonizes NMDAR function in an MHC-I- and TCR-independent manner•Blocking the B2M-NMDAR interaction corrects synaptic deficits in DS and aged mice β2-microglobulin dissociates from MHC-I complex, crosses the blood-brain barrier, antagonizes NMDA receptors, and impairs synaptic function under pathological conditions such as Down syndrome and aging.