N-Methyl-D-aspartate glutamate receptors (NMDARs) are involved in multiple physiopathological processes, including synaptic plasticity, neuronal network activities, excitotoxic events, and cognitive impairment. Abnormalities in NMDARs can initiate a cascade of pathological events, notably in Alzheimer’s disease (AD) and even other neuropsychiatric disorders. The subunit composition of NMDARs is plastic, giving rise to a diverse array of receptor subtypes. While they are primarily found in neurons, NMDAR complexes, comprising both traditional and atypical subunits, are also present in non-neuronal cells, influencing the functions of various peripheral tissues. Furthermore, protein-protein interactions within NMDAR complexes has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, all of which potentially served as an obligatory relay of cognitive impairment. Nonetheless, the precise mechanistic link remains to be fully elucidated. In this review, we provided an in-depth analysis of the structure and function of NMDAR, investigated their interactions with various pathogenic proteins, discussed the current landscape of NMDAR-based therapeutics, and highlighted the remaining challenges during drug development.

N-甲基-D-天冬氨酸谷氨酸受体(NMDAR) 参与多种病理生理过程，包括突触可塑性、神经元网络活动、兴奋性毒性事件和认知障碍。NMDAR 的异常可能引发一系列病理事件，特别是在阿尔茨海默病 (AD) 甚至其他神经精神疾病中。NMDAR 的亚基组成是可塑的，产生了多种受体亚型。虽然它们主要存在于神经元中，但包含传统和非典型亚基的 NMDAR 复合物也存在于非神经元细胞中，影响各种外周组织的功能。此外，NMDAR 复合物内的蛋白质-蛋白质相互作用与 Aβ 积累、tau 磷酸化、神经炎症和线粒体功能障碍有关，所有这些都可能成为认知障碍的必然中继。尽管如此，精确的机制联系仍有待充分阐明。在这篇综述中，我们深入分析了 NMDAR 的结构和功能，研究了它们与各种致病蛋白的相互作用，讨论了基于 NMDAR 的治疗的当前前景，并强调了药物开发过程中剩余的挑战。