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

项目描述（由申请人提供）：拟建项目计划开发一种预防阿尔茨海默病（AD）模型小鼠记忆丧失的新策略。该策略基于一个新概念，即选择性局部抑制蛋白酶体是有益的，并且可以防止淀粉样蛋白的有害影响。蛋白酶体是一种降解以泛素分子附着为标志的蛋白质水解复合物。（A?）长期突触可塑性。传统观点认为，在AD中，A？肽积累或其他原因导致AD损害泛素-蛋白酶体途径，蛋白水解缺陷加重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。利用海马后期长期增强（L-LTP）作为突触长期可塑性的模型系统，我们发现核蛋白酶体的抑制会损害突触的可塑性，而树突蛋白酶体的抑制则会改善突触的可塑性。因此，我们认为，尽管抑制神经元范围内或细胞核内的蛋白酶体肯定会加剧阿尔茨海默病的病理，但选择性抑制树突蛋白酶体将有助于改善阿尔茨海默病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一个蛋白质转导结构域（PTD），使其能够穿过质膜进入神经元。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良的A？并能恢复正常的L-LTP。由于PTD技术在行为学研究中的应用有局限性，现在我们计划开发腺相关病毒介导的海马体递送，以测试树突棘中蛋白酶体的选择性抑制是否可以挽救AD模型小鼠的记忆缺陷。这一探索性项目将为我们研究蛋白酶体在突触可塑性中的作用，为开发一种新的治疗策略来改善阿尔茨海默病的记忆丧失奠定基础。

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.