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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adls（可溶性AB寡聚物）在阿尔茨海默病的分子病因学中的作用。我们之前已经确定，addl是在阿尔茨海默病患者的大脑中积累的亚稳态神经毒素。尽管尚未得到证实，但这种积累越来越有可能导致阿尔茨海默病的早期记忆丧失。此外，我们实验室最近的研究结果表明，addl对神经元的影响可能为阿尔茨海默病的主要病理方面提供了统一的机制。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。当暴露于ADDLs时，神经元表现出与AD相关的三种主要病理：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addl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这三种病理联系起来。我们发现addl作为高亲和力的突触配体附着在神经元上，这是一种仅限于高n低聚物的功能增益，这是该机制的一个强有力的线索。我们的假设是ADDL与突触的连接是所有AD神经元病理共同的机制起点。具体的子目标包括确定突触连接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由ADDL结合触发的机制，最终导致突触变性。这个目标是特别重要的，因为突触丧失和阿尔茨海默氏痴呆症之间的相关性。ADDLs诱导的突触畸变包括NMDA受体的显著下调，突触棘形态出现不成熟，突触棘丰度显著降低。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，通过破坏f -肌动蛋白，过量的Arc积累是突触棘分子和结构退化机制的早期诱发步骤。该项目解决了全面表征adls在神经元中诱导的ad相关病理变化的需要，以确定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。预期的结果有可能为早期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阿尔茨海默病药物靶点，并为开发用于阿尔茨海默病治疗的新型神经保护化合物提供基于机制的分析。