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

• 批准号: 8319110
• 负责人: ASHOK N HEGDE
• 金额: $ 21万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319110
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' 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

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. PUBLIC HEALTH RELEVANCE: One of the first symptoms of Alzheimer's disease is memory loss. We have found that the memory impairment can be prevented if we manipulate protein degradation in nerve cells. Based on our findings, the research project will develop a new strategy for treatment of memory loss seen in Alzheimer's disease.

描述（由申请人提供）：拟议的项目计划开发一种新的策略，以防止阿尔茨海默病（AD）模型小鼠的记忆丧失。该策略是基于一个新的概念，选择性的蛋白酶体，蛋白水解复合物，降解蛋白质底物标记的泛素分子的附着，是有益的，可以防止有害的影响淀粉样蛋白？（A？）长期突触可塑性。传统观点认为，在AD中，由A？肽积累或AD的其它原因损害了遍在蛋白-蛋白酶体途径，并且蛋白水解缺陷加剧了AD。我们的非传统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的，往往是相反的功能。以海马晚时相长时程增强（L-LTP）为模型系统研究突触的长时程可塑性，我们发现抑制核蛋白酶体会损害突触的可塑性，而抑制树突状蛋白酶体则会改善突触的可塑性，因此我们认为，尽管抑制整个神经元或核内的蛋白酶体肯定会加重AD的病理，选择性抑制树突状蛋白酶体将有助于改善AD的突触缺陷和记忆障碍。为了验证这一想法，我们设计了一种新的策略，将重组蛋白酶体抑制剂特异性地靶向神经元中的树突棘。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，选择性抑制蛋白酶体在树突棘可以防止不利的A？影响L-LTP，并能恢复正常的L-LTP。由于PTD技术在行为研究中的应用存在局限性，现在我们计划开发腺相关病毒介导的海马递送，以测试是否选择性抑制树突棘中的蛋白酶体可以挽救AD模型小鼠的记忆缺陷。这个探索性的项目将奠定基础，翻译我们的研究的蛋白酶体在突触可塑性的作用，对开发一种新的治疗策略，改善记忆丧失的AD。 公共卫生相关性：阿尔茨海默病的最初症状之一是记忆力丧失。我们已经发现，如果我们控制神经细胞中的蛋白质降解，记忆障碍可以得到预防。根据我们的发现，该研究项目将开发一种新的策略来治疗阿尔茨海默病中的记忆丧失。