Elucidating a role for eEF2 phosphorylation in Alzheimer's Disease pathogenesis.

项目摘要/摘要 阿尔茨海默病(AD)是老年人中最常见的痴呆形式，有望成为一种新的 21世纪的流行病。目前尚无治愈阿尔茨海默病的方法或阻止其进展的方法。此外， 阿尔茨海默病的基本分子机制仍然难以捉摸。许多基本的细胞过程是 在阿尔茨海默病中受到影响，包括从头蛋白合成(信使核糖核酸翻译)的障碍。蛋白质合成是 长期记忆形成所必需的；翻译的几个方面在AD中是不受调节的。近期 证据表明AD模型小鼠脑内真核细胞延伸因子2(EEF2)活性下调 和人类阿尔茨海默病患者。在翻译过程中，eEF2介导氨酰-tRNA从 核糖体A-to P-位点。EEF2被其唯一已知的激酶-eEF2激酶(EEF2K)磷酸化，阻断eEF2 活性和抑制一般蛋白质的合成。人死后阿尔茨海默病中eEF2过度磷酸化 AD模型小鼠的脑和海马区。此外，调节eEF2K的信号通路有 与AD的发病机制有关。因此，这项提案的目标是确定是否禁止 EEF2K活性(以及随后的eEF2上调)缓解AD相关的蛋白质合成缺陷 和记忆的形成。该项目将利用一种基因方法，其中eEF2K活性在 Tg19959 AD模型小鼠。利用行为、电生理和生化方法，这些实验 本文将1)阐明抑制eEF2K活性是否能挽救AD模型中的记忆缺陷 2)确定抑制eEF2K是否能减轻AD相关突触可塑性损伤； 以及3)确定eEF2磷酸化减少是否改善了AD的病理，包括脑淀粉样蛋白 沉积和tau过度磷酸化。这里提出的实验将有助于阐明一部小说 阿尔茨海默病的病理生理学机制，潜在地揭示了新的治疗靶点。

Project Summary/Abstract Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is poised to become a new epidemic in the 21st century. There is currently no cure for AD or means to stop its progression. Moreover, the basic molecular mechanisms responsible for AD remain elusive. Many essential cellular processes are affected in AD, including impairment of de novo protein synthesis (mRNA translation). Protein synthesis is required for long-term memory formation; several aspects of translation are dysregulated in AD. Recent evidence shows eukaryotic elongation factor 2 (eEF2) activity is downregulated in the brains of AD model mice and human AD patients. During translation, eEF2 mediates the translocation of aminoacyl-tRNA from the ribosomal A- to P-site. Phosphorylation of eEF2 by its only known kinase, eEF2 kinase (eEF2K), blocks eEF2 activity and suppresses general protein synthesis. eEF2 is hyperphosphorylated in post mortem human AD brains and the hippocampi of AD model mice. Furthermore, the signaling pathways that regulate eEF2K have been implicated in AD pathogenesis. Thus, the objective of this proposal is to determine whether inhibition of eEF2K activity (and subsequent upregulation of eEF2) alleviates AD-associated deficits in protein synthesis and memory formation. This project will utilize a genetic approach in which eEF2K activity is downregulated in Tg19959 AD model mice. Using behavioral, electrophysiological, and biochemical methods, the experiments proposed here will 1) elucidate whether suppression of eEF2K activity rescues memory deficits in AD model mice; 2) determine whether inhibition of eEF2K can alleviate AD-associated synaptic plasticity impairments; and 3) establish whether reduction in eEF2 phosphorylation improves AD pathology, including brain amyloid deposition and tau hyperphosphorylation. The experiments proposed here will help elucidate a novel mechanism for AD pathophysiology, potentially shedding light on novel therapeutic targets.