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低聚物）在阿尔茨海默氏病的分子病因中所起的作用。我们先前确定ADDL是在阿尔茨海默氏症受影响的大脑中积累的可稳定神经毒素。尽管尚未得到证明，但这种积累越来越有可能导致AD的早期记忆丧失。此外，我们实验室的最新发现表明，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与AD病理学的这些重要新联系。当暴露于ADDL时，神经元表现出三种主要的病理敏捷性：AD：ROS的产生，Tau高磷酸化和突触变性。我们的第一个目的是确定ADDL如何启动这种神经元损害，以及一种共同的起始机理是否将所有三种病理联系起来。该机制的强烈线索是，我们的发现，即作为高亲和力突触配体附着在神经元上，这是限于高N低聚物的功能。我们的假设是，对突触上的附加附件是所有AD神经元病理共有的机械起点。特定的子iaM包括识别突触附着的分子性质及其在启动附加诱导的病理学中的作用。我们的第二个目的是确定由ADDL结合触发的机制，最终导致突触变性。由于突触丧失与阿尔茨海默氏症的痴呆症之间的相关性，该目标非常重要。 ADDL引起的突触像差包括NMDA受体的主要下调，未成熟的突触脊柱形态的出现以及突触脊柱丰度的显着降低。在此损害之前，ARC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-肌动蛋白而过度的ARC积累是负责突触棘分子和结构恶化的机制的早期煽动步骤。该项目解决了通过ADDL诱导的神经元引起的与AD相关的病理变化的需求，以定义构成该病理学的细胞和分子机制，并确定负责发起病原机制的最早事件。预期的结果有可能为早期AD病理和记忆力丧失提供统一的机制。该项目的成功完成应确定新的AD药物靶标，并为开发新型神经保护化合物的开发提供基于机制的测定方法。