| First Author | Gao Y | Year | 2023 |
| Journal | Cell | Volume | 186 |
| Issue | 5 | Pages | 1026-1038.e20 |
| PubMed ID | 36868208 | Mgi Jnum | J:340242 |
| Mgi Id | MGI:7446144 | Doi | 10.1016/j.cell.2023.01.021 |
| Citation | Gao Y, et al. (2023) beta2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. Cell 186(5):1026-1038.e20 |
| abstractText | 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 beta2-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. |
