Impairment of axonal transport by Amyloid precursor protein and amyloid Beta-prot

淀粉样前体蛋白和淀粉样β-prot对轴突运输的损害

基本信息

批准号：
8132465
负责人：
Lawrence S. Goldstein
金额：
$ 33.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132465
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animals Axon Axonal Transport Behavior Behavioral Binding Proteins Collaborations Defect Development Diagnostic Down Syndrome Elements Failure Gene Duplication Genetic Hippocampus (Brain)Human Impairment Kinesin Length Maintenance Methods Microtubules Mitochondria Modification Mouse Strains Movement Mus Mutation Neurofibrillary Tangles Neurons Organelles Pathology Pathway interactions Phenotype Play Poison Poisoning Process Production Protein C Protein Overexpression Proteins Proteolytic Processing Research Personnel Role Senile Plaques Signal Transduction Synapses Testing Toxic effect Transgenes Vesicle Work abeta toxicity amyloid precursor protein processing basal forebrain base cholinergic in vivo mutant neuronal transport neuropathology overexpression synaptic function tau Proteins

项目摘要

Amyloid precursor protein (APR) is a key player in the development of Alzheimer's Disease (AD) Mutations in humans that alter APR processing or overexpress APP appear to be sufficient to cause AD and to generate the amyloid plaques that are a constent feature of AD neuropathology. Although most work on AD development focuses on the potential toxicity of Abeta proteolytic fragments of APP, numerous observations point to significant neuronal defects caused by other APP proteolytic processing products or overexpression of full length APP itself. A consistent and long-standing set of observations suggest that a highly relevant phenotype caused by excess APP, which may also be found in early and late AD, is poisoning of the axonal transport machinery. This machinery is required for long-range neurotrophic signaling and for the supply of proteins and organelles needed for the maintenance of functional synapses. These observations also provide a way to tie APP behavior to the other major neuropathology found in AD, namely the neurofibrillary tangles, composed of the microtubule binding protein tau, which has also been implicated in controlling the transport of APP and other vesicles and organelles. Because overexpression of mutant forms of human APP in the mouse is one of the major models of AD, and because overexpression of APP may be sufficient to cause some forms of AD, it is crucial to understand the consequences of APP overexpression in neurons, and in particular how excess APP poisons axonal transport. Key issues include resolving whether Abeta plays a role in axonal transport defects and whether the defects generated by APP overexpression and Abeta toxicity are distinct. A related issue that needs to be evaluated further emerges from our recent observation that transport defects may enhance APP processing, potentially causing an autocatalytic spiral of defects. To understand the consequences of APP overexpression in neurons, and in particular how excess APP poisons axonal transport and to resolve whether Abeta plays a role in causing axonal transport defects we propose: 1) To test the hypothesis that APP controls its own transport in "cis". 2) To test the hypothesis that increased APP or its processing products poisons transport in trans and consequently affects synaptic function, and behavior. 3) To test the hypothesis that reduced transport enhances APP processing in neurons.

淀粉样前体蛋白（APR）是阿尔茨海默氏病（AD）突变发展的关键参与者在更改APR处理或过表达应用的人类中似乎足以引起AD和产生淀粉样蛋白斑块，这是AD神经病理学的坚定特征。虽然大多数在广告上工作开发重点是App的Abeta蛋白水解片段的潜在毒性，许多观察结果指出由其他APP蛋白水解处理产物或过表达引起的明显神经元缺陷全长应用本身。一致且长期存在的观察结果表明，高度相关由多余的应用程序引起的表型（也可以在AD早期和晚期中发现）中毒运输机械。该机械是远程神经营养信号传导所必需的维持功能突触所需的蛋白质和细胞器。这些观察也是如此提供一种将应用程序行为与AD中发现的其他主要神经病理学联系起来的方法，即神经纤维缠结，由微管结合蛋白tau组成，这也与控制有关应用程序和其他囊泡和细胞器的运输。因为人类突变形式的过表达鼠标中的应用是AD的主要模型之一，因为APP的过表达可能就足够了为了引起某些形式的AD，了解神经元中应用过表达的后果至关重要，特别是Apps Poisons轴突运输方式。关键问题包括解决Abeta是否在轴突传输缺陷中起作用，以及应用程序过表达产生的缺陷和 Abeta毒性是不同的。需要评估的相关问题进一步出现了我们最近的观察到运输缺陷可能会增强应用程序处理，并可能导致自催化螺旋缺陷。了解神经元中应用过表达的后果，尤其是如何多余的应用毒药轴突运输并解决Abeta是否在引起轴突运输方面起作用我们提出的缺陷：1）测试App控制其自身运输在“顺式”的假设。 2）测试假设增加了应用程序或其加工产品毒药在反式中的运输，因此会影响突触功能和行为。 3）测试降低运输的假设可增强应用程序处理在神经元中。