2. Academic Validation
  3. β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function

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

  • Cell. 2023 Mar 2;186(5):1026-1038.e20. doi: 10.1016/j.cell.2023.01.021.
Yue Gao 1,  Yujuan Hong 2,  Lihong Huang 2,  Shuang Zheng 2,  Haibin Zhang 2,  Shihua Wang 2,  Yi Yao 3,  Yini Zhao 2,  Lin Zhu 2,  Qiang Xu 2,  Xuhui Chai 2,  Yuanyuan Zeng 4,  Yuzhe Zeng 2,  Liangkai Zheng 5,  Yulin Zhou 5,  Hong Luo 2,  Xian Zhang 2,  Hongfeng Zhang 1,  Ying Zhou 4,  Guo Fu 6,  Hao Sun 2,  Timothy Y Huang 7,  Qiuyang Zheng 1,  Huaxi Xu 8,  Xin Wang 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurology, the First Affiliated Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurology, the First Affiliated Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
  • 3 Department of Functional Neurosurgery, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361003, China.
  • 4 National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
  • 5 United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen 361103, China.
  • 6 State Key Laboratory of Cellular Stress Biology, Cancer Research Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
  • 7 Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 8 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China; Institute for Brain Science and Disease, Chongqing Medical University, Chongqing 400016, China.
  • 9 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurology, the First Affiliated Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China. Electronic address: wangx@xmu.edu.cn.
PMID: 36868208 DOI: 10.1016/j.cell.2023.01.021
Abstract

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.

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