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

阐明 eEF2 磷酸化在阿尔茨海默病发病机制中的作用。

• 批准号: 9327134
• 负责人: Brenna Beckelman
• 金额: $ 4.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2018-10-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327134
• 关键词: Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acyl Transfer RNA; Amyloid beta-Protein; Amyloid deposition; Animal Disease Models; Behavioral; Biochemical; Biological Assay; Brain; Brain Diseases; Cell model; Cell physiology; Defect; Dementia; Disease; Elderly; Electrophysiology (science); Epidemic; Event; Functional disorder; Genetic; Genetic Suppression; Genetic Translation; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intervention; Knockout Mice; Learning; Light; Long-Term Potentiation; Measures; Mediating; Memory; Memory Loss; Memory impairment; Methods; Molecular; Mus; Mutant Strains Mice; Neurons; Pathogenesis; Pathologic; Pathology; Patients; Peptide Elongation Factor 2; Pharmacology; Phosphorylation; Phosphotransferases; Play; Protein Biosynthesis; Proteins; Reporting; Research; Ribosomes; Role; Short-Term Memory; Signal Pathway; Site; Slice; Synapses; Synaptic plasticity; Syndrome; Testing; Translations; Treatment Efficacy; Up-Regulation; Western Blotting; abeta deposition; base; brain tissue; calmodulin-dependent protein kinase III; experimental study; genetic approach; improved; kinase inhibitor; long term memory; morris water maze; mouse model; new therapeutic target; novel; object recognition; peptidyl-tRNA; prevent; spatial memory; tau Proteins

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.

项目总结/摘要 阿尔茨海默病（AD）是老年人中最常见的痴呆形式，并且有望成为一种新的 21世纪世纪的流行病。目前还没有治愈AD或阻止其进展的方法。而且 导致AD的基本分子机制仍然难以捉摸。许多重要的细胞过程 在AD中受影响，包括从头蛋白质合成（mRNA翻译）受损。蛋白质合成 长期记忆形成所需; AD中翻译的几个方面失调。最近 证据显示真核细胞延伸因子2（eEF 2）活性在AD模型小鼠的脑中下调 和人类AD患者。在翻译过程中，eEF 2介导氨酰-tRNA从细胞膜上转位， 核糖体A-至P-位点。eEF 2通过其唯一已知的激酶eEF 2激酶（eEF 2K）磷酸化，阻断eEF 2 活性并抑制一般蛋白质合成。eEF 2在人死后AD中过度磷酸化 AD模型小鼠的脑和海马。此外，调节eEF 2K的信号通路具有以下特征： 与AD发病机制有关。因此，本建议的目的是确定是否抑制 eEF 2K活性（以及随后的eEF 2上调）可缓解AD相关的蛋白质合成缺陷 和记忆的形成。该项目将利用一种遗传方法，其中eEF 2K活性下调， Tg 19959 AD模型小鼠。利用行为学、电生理学和生物化学方法， 本文提出的方法将1）阐明抑制eEF 2K活性是否能挽救AD模型中的记忆缺陷 2）确定抑制eEF 2K是否可以减轻AD相关的突触可塑性损伤; 和3）确定eEF 2磷酸化的减少是否改善AD病理学，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 AD的病理生理机制，可能揭示新的治疗靶点。