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

描述（由申请人提供）：本项目的长期目标是了解ADDL（可溶性AB寡聚体）在阿尔茨海默病分子病因学中所起的作用。我们先前确定ADDL是亚稳态神经毒素，积累在阿尔茨海默氏症影响的大脑。虽然尚未得到证实，但这种积累越来越有可能导致AD的早期记忆丧失。此外，我们实验室的最新研究结果表明，ADDL对神经元的影响可以为AD病理学的主要方面提供统一的机制。我们建议在分子机制水平上研究这些重要的新联系。当暴露于ADDL时，神经元表现出与AD密切相关的三种主要病理：ROS产生、tau蛋白过度磷酸化和突触变性。我们的第一个目标是确定ADDLs如何启动这种神经元损伤，以及是否有一个共同的启动机制将所有三种病理联系起来。一个强有力的线索的机制是我们发现，ADDL附着到神经元作为高亲和力的突触配体，一个获得的功能限于高n寡聚体。我们的假设是，ADDL连接到突触是共同的所有AD神经元病理的机械起点。具体的子目标包括识别突触附着的分子性质及其在启动ADDL诱导的病理中的作用。我们的第二个目标是确定ADDL结合引发的最终导致突触变性的机制。由于突触丧失和阿尔茨海默氏痴呆症之间的相关性，这一目标特别重要。由ADDL诱导的突触畸变包括NMDA受体的主要下调、不成熟突触棘形态的出现以及突触棘丰度的显著降低。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，其适当的瞬时表达是长期记忆形成所必需的。我们的假设是，过度的弧积累，破坏F-肌动蛋白，是一个早期的煽动步骤的机制负责的分子和结构退化的突触棘。该项目解决了需要全面表征ADDLs在神经元中诱导的AD相关病理变化，以定义该病理基础的细胞和分子机制，并确定负责启动致病机制的最早事件。预期结果有可能为早期AD病理和记忆丧失提供统一的机制。该项目的成功完成将确定新的AD药物靶点，并为开发可用于AD治疗的新型神经保护化合物提供基于机制的测定。

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.