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

美国的老年人口正在增长，因此治疗与年龄相关的新疗法 失忆是保护个人独立性和减轻阿尔茨海默病负担所必需的 (Ad)。NMDARs是正常学习所必需的NMDARs 和记忆，但NMDAR靶向疗法在减轻AD严重程度方面效果甚微 症状，不被批准用于治疗非病理性脑老化中的记忆力丧失。NMDAR是 在GluN1和GluN2亚基之间形成的生化多样性的四聚体。GluN2A和GluN2B亚型 在海马区大量表达，但针对GluN2A或GluN2B的选择性配体 对NMDAR在整个生命周期内对记忆和神经功能的贡献产生了相互矛盾的描述。 尚未探索的是含有GluN1、GluN2A和GluN2B的三异构体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 GluN1/GluN2A/GluN2B三异构体NMDAR，并研究如何在自然和实验中发生 GluN2亚型的诱导变化调节衰老大脑中三异构体的形成。这些研究 将具有重大意义，因为他们将创造新的工具来瞄准更广泛的自然发生 异构体NMDAR，并确定GluN2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靶向疗法开辟新的途径 能有效防止或逆转在衰老后期出现的记忆力丧失。

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.