Memory-Related Protein Synthesis in Alzheimer's Disease Mouse Models

阿尔茨海默病小鼠模型中记忆相关的蛋白质合成

• 批准号: 8975046
• 负责人: Leon Reijmers
• 金额: $ 24.75万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975046
• 关键词: Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Binding; Brain; Caregivers; Cells; Cerebral Ventricles; Dendrites; Development; Elements; Emotional; Functional disorder; Future; Green Fluorescent Proteins; Hippocampus (Brain); Home environment; Hour; Immunoprecipitation; Injection of therapeutic agent; Lead; Measures; Mediating; Memory; Memory Loss; Messenger RNA; Methods; Microdissection; Molecular; Mus; Mutation; Neurons; Pathway interactions; Patients; Physiological; Physiology; Positioning Attribute; Preparation; Process; Production; Protein Biosynthesis; Proteins; Regulation; Ribosomal Proteins; Ribosomes; Role; Sampling; Site; Staging; Synapses; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; base; behavior test; brain tissue; conditioned fear; design; dimer; drug candidate; endophenotype; fear memory; genome-wide; hippocampal pyramidal neuron; in vivo; monomer; mouse model; neuronal cell body; new therapeutic target; next generation sequencing; novel strategies; prevent; protein expression; public health relevance; therapeutic target

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by a severe loss of memories that causes great emotional suffering for patients and caregivers. There is currently no treatment for AD associated memory loss, because of insufficient understanding of the molecular mechanism that causes this memory loss. Memory loss is present during early stages of AD. There is growing evidence that memory loss during the early stages of AD is caused by effects of soluble amyloid-beta (Abeta) oligomers on synapses. Since protein synthesis is essential for both memory storage and normal synapse physiology, altered protein synthesis provides a plausible molecular mechanism for mediating the effects of soluble Abeta oligomers on memories and synapses. This project will determine if soluble Abeta oligomers impair protein synthesis associated with memory storage. To achieve this, an AD mouse model based on the intracerebroventricular injection of Abeta oligomers will be used. Intracerebroventricular injection of Abeta oligomers acutely impairs the formation of a contextual fear memory. In addition, a transgenic AD mouse model will be studied. These AD mouse models will be combined with a unique transgenic mouse that was designed for the explicit purpose of measuring protein synthesis during memory storage. This transgenic mouse enables the isolation of translated mRNA from neurons in the hippocampus by expressing tagged ribosomes. By sequencing the mRNA associated with the tagged ribosomes, the synthesis rate of all neuronal proteins can be determined. By using this unbiased genome-wide approach, new unanticipated therapeutic targets can be discovered. Since the molecular pathway responsible for AD associated memory loss might also contribute to the progression of AD, these therapeutic targets might slow down or even prevent the progression of AD.

 描述（由申请人提供）：阿尔茨海默病（AD）的特征是严重的记忆丧失，给患者和护理人员造成巨大的情感痛苦。目前没有治疗AD相关的记忆丧失，因为对导致这种记忆丧失的分子机制的理解不足。AD的早期阶段存在记忆丧失。越来越多的证据表明，AD早期阶段的记忆丧失是由可溶性淀粉样蛋白β（Abeta）寡聚体对突触的影响引起的。由于蛋白质合成对于记忆储存和正常突触生理都是必不可少的，因此蛋白质合成的改变为介导可溶性Abeta寡聚体对记忆和突触的影响提供了一种合理的分子机制。该项目将确定可溶性Abeta寡聚体是否损害与记忆存储相关的蛋白质合成。为了实现这一点，将使用基于脑室内注射Abeta寡聚体的AD小鼠模型。脑室内注射Abeta寡聚体急性损害了背景恐惧记忆的形成。此外，将研究转基因AD小鼠模型。这些AD小鼠模型将与独特的转基因小鼠组合，该转基因小鼠被设计用于测量记忆储存期间蛋白质合成的明确目的。这种转基因小鼠能够通过表达标记的核糖体从海马中的神经元分离翻译的mRNA。通过对与标记的核糖体相关的mRNA进行测序，可以确定所有神经元蛋白质的合成速率。通过使用这种无偏见的全基因组方法，可以发现新的意想不到的治疗靶点。由于负责AD相关记忆丧失的分子途径也可能有助于AD的进展，因此这些治疗靶点可能减缓甚至阻止AD的进展。