Precision Targeting of Heteromeric NMDA Receptors in Age-Related Memory Disorders

美国的老年人口正在增长，因此新的治疗方法可以治疗与年龄相关的疾病。 记忆丧失是保护个人独立和减轻阿尔茨海默病负担所必需的 （AD）。离子型谷氨酸受体的NMDA亚型（NMDARs）是必要的正常学习 和记忆，但NMDAR靶向治疗在减轻AD的严重程度方面效果甚微 症状，并且未被批准用于治疗非病理性脑老化中的记忆丧失。NMDAR是 在GluN 1和GluN 2亚基之间形成生物化学上不同的四聚体。GluN 2A和GluN 2B亚型 在海马体中大量表达，但靶向GluN 2A或GluN 2B的选择性配体具有 NMDAR对记忆和神经功能的贡献产生了相互矛盾的说法。 未探索的是含有GluN 1，GluN 2A和GluN 2B的三异聚体NMDAR的贡献。这 该项目将通过开发对NMDAR具有选择性的新配体来创新NMDAR的科学研究。 GluN 1/GluN 2A/GluN 2B三聚体NMDAR，并研究如何自然发生和实验 GluN 2同种型的诱导变化调节衰老脑中三异聚体的形成。这些研究 将是重要的，因为他们将创造新的工具，以针对更广泛的自然发生的 异聚体NMDAR，并确定GluN 2亚型之间的相互作用如何影响神经功能， 大脑老化最终，这些发现将为开发NMDAR靶向疗法开辟新途径 有效预防或逆转老年人出现的记忆丧失。

The senior citizen population in the United States is growing, so new therapeutics to treat age-related memory loss are needed to protect personal independence and reduce the burden of Alzheimer’s disease (AD). Ionotropic glutamate receptors of the NMDA subtype (NMDARs) are necessary for normal learning and memory, but NMDAR-targeting therapeutics are minimally effective in lessening the severity of AD symptoms and are not approved to treat memory loss in non-pathological brain aging. NMDARs are biochemically diverse tetramers formed between GluN1 and GluN2 subunits. GluN2A and GluN2B isoforms are abundantly expressed in the hippocampus, but selective ligands that target GluN2A or GluN2B have produced conflicting accounts of NMDAR contribution to memory and neural functions over the lifespan. Unexplored are contributions of tri-heteromeric NMDARs that contain GluN1, GluN2A and GluN2B. This project will innovate the scientific study of NMDARs by developing new ligands that are selective for the GluN1/GluN2A/GluN2B tri-heteromeric NMDAR and investigate how naturally occurring and experimentally induced changes in GluN2 isoforms regulate formation of tri-heteromers in the aging brain. These studies will be significant because they will create new tools to target a broader range of naturally occurring heteromeric NMDARs and identify how interactions between GluN2 isoforms influence neural function in brain aging. Ultimately, these discoveries will open new avenues to develop NMDAR-targeting therapeutics that are effective in preventing or reversing memory loss that emerges in advanced aging.