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Role of protein synthesis in Alzheimers disease-associated impairments of synaptic plasticity and memory

蛋白质合成在阿尔茨海默病相关的突触可塑性和记忆损伤中的作用

基本信息

批准号：
10180826
负责人：
Tao Ma
金额：
$ 46.43万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180826
关键词：
AD transgenic mice APP-PS1 Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amino Acids Amyloid beta-Protein Biochemical Biological Assay Brain Cognition Disorders Cognitive Cognitive deficits Data Defect Dementia Deterioration Development Disease Electrophysiology (science)Etiology Event Failure Foundations Frontotemporal Dementia Functional disorder Future Genetic Genetic Translation Goals Hippocampus (Brain)Human Imaging Techniques Impairment Knock-out Knowledge Learning Location Long-Term Potentiation Mass Spectrum Analysis Mediating Memory Memory impairment Messenger RNA Methods Modeling Molecular Mus Neurodegenerative Disorders Neurosciences Pathogenesis Peptide Elongation Factor 2 Pharmacology Phase Phosphorylation Phosphotransferases Prion Diseases Protein Biosynthesis Proteins Proteomics Reporting Repression Research Ribosomes Role Sampling Signal Transduction Site Slice Structure Surface Synapses Synaptic plasticity Syndrome Testing Therapeutic Translations Work base behavior test confocal imaging design diagnostic biomarker effective therapy experimental study genetic approach genetic testing improved inhibitor/antagonist knock-down morris water maze mouse genetics mouse model novel novel diagnostics peptidyl-tRNA prevent restoration small molecule inhibitor synaptic failure synaptic function therapeutic target water maze

项目摘要

The basic cellular/molecular signaling mechanisms underlying Alzheimer’s disease (AD) pathophysiology are not well understood; this gap in knowledge is hampering our ability to find any effective therapies. Accumulating evidence indicates impaired synaptic function as a key event in AD pathogenesis. However, the molecular mechanisms underlying AD-associated synaptic dysfunction/failure remain elusive. We recently reported hyperphosphorylation of mRNA translational factor eukaryotic elongation factor 2 (eEF2) in AD brains. Phosphorylation of eEF2 by its (only known) kinase eEF2K results in repression of de novo protein synthesis, which is essential for long-lasting forms of synaptic plasticity and memory. Driven by the preliminary data, the central hypothesis to be tested in this application is that restoration of the capacity for de novo protein synthesis, via inhibition of eEF2K and thus eEF2 phosphorylation, will alleviate AD-associated synaptic failure and memory impairments. Three specific aims have been designed to test this hypothesis. Aim 1 seeks to determine whether restoration of normal eEF2 phosphorylation, via suppressing eEF2K activity, can rescue AD-associated impairments in hippocampal long-term synaptic plasticity. Aim 2 is to determine whether inhibition of eEF2K activity improves learning and memory deficits in AD mouse model. Aim 3 is to determine whether AD-associated impairments of de novo protein synthesis can be mitigated by inhibiting eEF2 kinase activity. The project proposes in-depth analyses using multiple state-of-art methods in neuroscience, including synaptic electrophysiology, confocal imaging, mouse genetics, and behavioral tests. We will also employ two new types of non-radioactive methods to assess de novo protein synthesis in brain slices: surface sensing of translation (SUnSET) and bioorthogonal noncanonical amino acid tagging (BONCAT). These novel methods will be combined with mass spectrometry/proteomics approach to reveal identities of proteins in AD brains whose synthesis is dysregulated because of abnormal eEF2K/eEF2 signaling. Findings from this project will contribute important data regarding the cellular/molecular signaling mechanisms underlying AD pathogenesis. Future studies will build on the results from this project and our other research findings on AD-related protein synthesis dysregulation to inform eventual development of novel diagnostic markers and better therapeutic strategies for AD-related cognitive syndromes, for which no effective treatments exist.

阿尔茨海默病（AD）病理生理的基本细胞/分子信号机制是