A Novel Strategy for Treating Memory Impairment in an Alzheimer's Disease Model

治疗阿尔茨海默病模型记忆障碍的新策略

基本信息

批准号：
8456076
负责人：
ASHOK N HEGDE
金额：
$ 17.48万
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：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8456076
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Animal Model Behavioral Biological Models Brain Cell Nucleus Cell membrane Cognitive deficits Complex Data Defect Dendrites Dendritic Spines Dependovirus Deposition Development Event Functional disorder Goals Hippocampus (Brain)Lactones Long-Term Potentiation Mediating Membrane Memory Memory Loss Memory impairment Mus Nerve Degeneration Neurofibrillary Tangles Neurons Nuclear Pathology Pathway interactions Patients Peptides Phase Proteasome Inhibition Proteasome Inhibitor Protein Biosynthesis Proteins Proteolysis Recombinants Research Research Project Grants Role Signal Pathway Sirolimus Site Slice Staging Symptoms Synapses Synaptic plasticity Techniques Testing Therapeutic Translating Ubiquitin base improved inhibitor/antagonist innovation long term memory mTOR protein multicatalytic endopeptidase complex novel novel strategies novel therapeutics prevent protein degradation small molecule spinophilin stem success synaptic function treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The proposed project plans to develop a new strategy to prevent memory loss in Alzheimer's disease (AD) model mice. The strategy is based on a novel concept that selective local inhibition of the proteasome, a proteolytic complex that degrades protein substrates marked by attachment of ubiquitin molecules, is beneficial and can prevent the harmful effects of amyloid ? (A?) on long-term synaptic plasticity. The conventional wisdom is that in AD, pathological changes brought about by A? peptide accumulation or other causes of AD impair the ubiquitin- proteasome pathway and defective proteolysis exacerbates AD. Our unconventional approach stems from our observation that the proteasome performs different and often opposite functions in different parts of the neuron. Using hippocampal late phase long-term potentiation (L-LTP) as a model system for long-term synaptic plasticity, we found that inhibition of the nuclear proteasome impairs synaptic plasticity, while inhibition of th dendritic proteasome improves it. Therefore, we believe that although inhibition of the proteasome neuron-wide or in the nucleus would certainly exacerbate AD pathology, selective inhibition of the dendritic proteasome would help ameliorate synaptic deficits and memory impairment in AD. To test this idea, we devised a novel strategy to target a recombinant proteasome inhibitor specifically to dendritic spines in neurons. This recombinant inhibitor has a protein transduction domain (PTD) that enables it to traverse across the plasma membrane and enter neurons. Our preliminary data show that selective inhibition of the proteasome in dendritic spines can prevent the adverse A? effects on L-LTP and can restore normal L-LTP. Because the PTD technique has limitations for use in behavioral studies, now we plan to develop adeno-associated virus-mediated delivery into the hippocampus to test whether selective inhibition of the proteasome in dendritic spines can rescue memory deficits in AD model mice. This exploratory project will lay the groundwork for translating our research on the role of the proteasome in synaptic plasticity towards development of a new therapeutic strategy for ameliorating memory loss in AD.

描述（由申请人提供）：拟议项目计划开发一种新策略来预防阿尔茨海默病（AD）模型小鼠的记忆丧失。该策略基于一个新概念，即选择性局部抑制蛋白酶体（一种降解以泛素分子附着为标志的蛋白质底物的蛋白水解复合物）是有益的，并且可以防止淀粉样蛋白的有害影响？（A？）关于长期突触可塑性。传统观点认为，在AD中，A?带来的病理变化是由A?肽积累或 AD 的其他原因会损害泛素-蛋白酶体途径，并且蛋白水解缺陷会加剧 AD。我们的非常规方法源于我们的观察，即蛋白酶体在神经元的不同部分执行不同且通常相反的功能。使用海马晚期长时程增强（L-LTP）作为长期突触可塑性的模型系统，我们发现核蛋白酶体的抑制会损害突触可塑性，而树突蛋白酶体的抑制会改善突触可塑性。因此，我们相信，尽管抑制神经元范围内或细胞核中的蛋白酶体肯定会加剧AD病理，但选择性抑制树突状蛋白酶体将有助于改善AD中的突触缺陷和记忆障碍。为了测试这个想法，我们设计了一种新策略，将重组蛋白酶体抑制剂特异性靶向神经元的树突棘。这种重组抑制剂具有蛋白转导结构域 (PTD)，使其能够穿过质膜并进入神经元。我们的初步数据表明，选择性抑制树突棘中的蛋白酶体可以预防不利的A？对 L-LTP 产生影响，并能恢复正常的 L-LTP。由于 PTD 技术在行为研究中的使用存在局限性，现在我们计划开发腺相关病毒介导的递送至海马体，以测试选择性抑制树突棘中的蛋白酶体是否可以挽救 AD 模型小鼠的记忆缺陷。这个探索性项目将为将我们关于蛋白酶体在突触可塑性中的作用的研究转化为开发改善 AD 记忆丧失的新治疗策略奠定基础。