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

ADDL、突触

基本信息

批准号：
7615522
负责人：
WILLIAM L KLEIN
金额：
$ 30.34万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615522
关键词：
Address Affect Affinity Alzheimer&apos s Disease Amyloid Amyloid Fibrils Animal Model Appearance Binding Brain Cell Death Cell membrane Cellular biology Cerebrum Cognitive Cytoskeletal Proteins Dementia Dendritic Spines Deposition Deterioration Disease Down-Regulation Drug Delivery Systems EphB2 Receptor Etiology Event Excision F-Actin Failure Generations Goals Hippocampus (Brain)Immediate-Early Genes Impairment In Situ Insulin Insulin Receptor Insulin Resistance Investigation Laboratories Lead Learning Ligands Link Memory Memory Loss Mental Retardation Modeling Molecular Morphology N-Methyl-D-Aspartate Receptors Nature Neurologic Neurons Neurotoxins Pathogenesis Pathology Pathway interactions Patients Play Proteins Rattus Receptor Down-Regulation Resistance Role Shapes Signal Pathway Signal Transduction Source Staging Structure Surface Synapses Synaptic plasticity Synaptosomes Therapeutic Toxic effect Toxin Validation Vertebral column Work assay development base design gain of function insight long term memory novel oxidative damage prevent receptor research study response tau Proteins tau phosphorylation trafficking

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是了解 ADDL（可溶性 AB 寡聚物）在阿尔茨海默病的分子病因学中所发挥的作用。我们之前确定 ADDL 是亚稳态神经毒素，会在阿尔茨海默病患者的大脑中积聚。尽管尚未得到证实，但这种累积可能导致 AD 早期记忆丧失的可能性越来越大。此外，我们实验室的最新研究结果表明，ADDL 的神经元影响可以为 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与 AD 病理学的重要新联系。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 生成、tau 蛋白过度磷酸化和突触变性。我们的首要目标是确定 ADDL 如何引发这种神经元损伤，以及是否存在共同的引发机制将所有三种病理联系起来。该机制的一个有力线索是我们发现 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 寡聚物的功能获得。我们的假设是 ADDL 对突触的附着是所有 AD 神经元病理学共同的机制起点。具体的子目标包括识别突触附着的分子性质及其在引发 ADDL 诱导的病理中的作用。我们的第二个目标是确定 ADDL 结合触发最终导致突触退化的机制。由于突触丢失与阿尔茨海默氏痴呆之间的相关性，这一目标特别重要。 ADDL 引起的突触畸变包括 NMDA 受体的大幅下调、突触棘形态不成熟的出现以及突触棘丰度的显着降低。在这种损伤之前，Arc 会过度积累，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，通过破坏 F-肌动蛋白，过度的 Arc 积累是导致突触棘分子和结构退化的机制的早期诱发步骤。该项目解决了全面表征 ADDL 在神经元中诱导的 AD 相关病理变化的需要，定义这种病理学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 病理学和记忆丧失提供统一的机制。该项目的成功完成应确定新的 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分析。