ADDLs, synapses & the molecular etiology of Alzheimer's disease

描述(申请人提供)：该项目的长期目标是了解ADDLS(可溶性AB寡聚体)在阿尔茨海默病的分子病因学中所起的作用。我们之前已经确定ADDLS是一种亚稳态神经毒素，积聚在阿尔茨海默氏症患者的大脑中。虽然还没有得到证实，但这种积累可能导致AD早期记忆丧失的可能性越来越大。此外，我们实验室的最新发现表明，ADDLS对神经元的影响可能为AD病理的主要方面提供一个统一的机制。我们建议在分子机制水平上研究这些与AD病理的重要新联系。当神经元暴露于ADDLS时，表现出与AD密切相关的三种主要病理过程：ROS生成、tau过度磷酸化和突触变性。我们的第一个目标是确定ADDLS是如何启动这种神经元损伤的，以及是否有一个共同的启动机制将这三种病理联系在一起。机制的一个强有力的线索是我们发现ADDL作为高亲和力突触配体附着在神经元上，这是一种仅限于高n寡聚体的功能增益。我们的假设是，突触的ADT1连接是所有AD神经元病理学的共同机制起点。具体的亚目标包括确定突触附着的分子性质及其在启动ADTL诱导的病理中的作用。我们的第二个目标是确定由Add1结合触发的最终导致突触变性的机制。这一目标特别重要，因为突触丢失和阿尔茨海默氏症之间存在相关性。ADDLS引起的突触异常包括NMDA受体的显著下调、未成熟突触棘突形态的出现和突触棘突丰度的显著降低。在这种损伤之前是Arc的过度积累，Arc是一种突触F-肌动蛋白调节蛋白，其正确的瞬时表达是长期记忆形成所必需的。我们的假设是，过度的Arc积聚，通过破坏F-肌动蛋白，是导致突触脊椎分子和结构恶化的机制中的早期启动步骤。该项目致力于全面描述ADDLS诱导的神经元中AD相关的病理变化，以确定这种病理基础的细胞和分子机制，并确定启动致病机制的最早事件。预期的结果有可能为早期AD病理和记忆丧失提供一个统一的机制。该项目的成功完成将确定新的AD药物靶点，并为开发用于AD治疗的新的神经保护化合物提供基于机制的分析。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the role played by ADDLs (soluble AB oligomers) in the molecular etiology of Alzheimer's disease. We previously established that ADDLs are metastable neurotoxins that accumulate in Alzheimer's-affected brain. Though not yet proven, it is increasingly likely that this accumulation may cause AD's early memory loss. Recent findings from our laboratory suggest, moreover, that the neuronal impact of ADDLs could provide a unifying mechanism for major facets of AD pathology. We propose to investigate these important new links to AD pathology at the level of molecular mechanisms. When exposed to ADDLs, neurons manifest three major pathologies germane to AD: ROS generation, tau hyperphosphorylation and synapse degeneration. Our first aim is to determine how ADDLs initiate this neuronal damage and whether a common mechanism of initiation links all three pathologies. A strong clue to the mechanism is our finding that ADDLs attach to neurons as high-affinity synaptic ligands, a gain-of- function restricted to high-n oligomers. Our hypothesis is that ADDL attachment to synapses is the mechanistic starting point common to all AD neuronal pathology. Specific subaims include identifying the molecular nature of synaptic attachment and its role in initiating ADDL-induced pathologies. Our second aim is to determine the mechanism, triggered by ADDL binding that ultimately results in synaptic degeneration. This objective is of particular importance because of the correlation between synapse loss and Alzheimer's dementia. Synaptic aberrations induced by ADDLs include major down-regulation of NMDA receptors, appearance of immature synaptic spine morphology, and significant decrease in synaptic spine abundance. Preceding this damage is an excessive accumulation of Arc, a synaptic F-actin regulating protein whose proper transient expression is required for long-term memory formation. Our hypothesis is that excessive Arc accumulation, by disrupting F-actin, is an early instigating step in the mechanism responsible for molecular and structural deterioration of synaptic spines. This project addresses the need to comprehensively characterize AD-relevant pathological changes induced in neurons by ADDLs, to define the cellular and molecular mechanisms that underlie this pathology, and to identify the earliest events responsible for initiating pathogenic mechanisms. Anticipated results have the potential to provide a unifying mechanism for early AD pathology and memory loss. Successful completion of the project should identify new AD drug targets and provide mechanism-based assays for development of novel neuroprotective compounds useful for AD therapeutics.