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.

唐氏综合症（DS）是一种神经系统疾病，具有多种免疫相关症状；然而，中枢神经系统和外周免疫系统之间的串扰仍未被探索。通过联体共生和血浆输注，我们发现血源性因素会导致 DS 中的突触缺陷。蛋白质组学分析显示，人 DS 血浆中 β2-微球蛋白 (B2M) 升高，β2-微球蛋白 (B2M) 是 I 类主要组织相容性复合体 (MHC-I) 成分。在野生型小鼠中全身施用 B2M 会导致与 DS 小鼠中观察到的相似的突触和记忆缺陷。此外， B2m的基因消融或抗 B2M 抗体的全身给药可以抵消 DS 小鼠的突触损伤。从机制上讲，我们证明 B2M 通过与 GluN1-S2 环相互作用来拮抗 NMDA 受体 (NMDAR) 功能；使用竞争性肽阻断 B2M-NMDAR 相互作用可恢复 NMDAR 依赖性突触功能。我们的研究结果确定 B2M 是一种内源性 NMDAR 拮抗剂，并揭示了循环 B2M 在 DS 和相关认知障碍的 NMDAR 功能障碍中的病理生理学作用。