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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) 是阿尔茨海默病 (AD) 突变发展的关键因素在人类中，改变 APR 处理或过度表达 APP 似乎足以引起 AD 并产生淀粉样斑块，这是 AD 神经病理学的一个固有特征。虽然大部分工作都在AD上开发重点是 APP 的 Abeta 蛋白水解片段的潜在毒性，大量观察结果指出由其他 APP 蛋白水解加工产物或过度表达引起的显着神经元缺陷完整长度的APP本身。一系列一致且长期的观察表明，高度相关的 APP过量引起的表型，也可能出现在AD早期和晚期，是轴突中毒运输机械。这种机制是长程神经营养信号传导和供应维持功能性突触所需的蛋白质和细胞器。这些观察也提供了一种将 APP 行为与 AD 中发现的其他主要神经病理学（即神经原纤维）联系起来的方法缠结，由微管结合蛋白 tau 组成，也与控制 APP 和其他囊泡和细胞器的运输。因为人类突变体的过度表达小鼠中的 APP 是 AD 的主要模型之一，并且因为 APP 的过度表达可能就足够了要引起某些形式的 AD，了解 APP 在神经元中过度表达的后果至关重要，特别是过量的 APP 如何毒害轴突运输。关键问题包括解决 Abeta 是否 APP 过表达产生的缺陷是否在轴突运输缺陷中发挥作用 Abeta 的毒性是明显的。我们最近提出了一个需要进一步评估的相关问题观察到传输缺陷可能会增强 APP 处理，可能导致自催化螺旋的缺陷。了解神经元中 APP 过度表达的后果，特别是如何过量的 APP 会毒害轴突运输，并确定 Abeta 是否在引起轴突运输中发挥作用我们提出的缺陷： 1）检验APP在“cis”中控制自己的传输的假设。 2) 测试假设增加的 APP 或其加工产品会毒害反式运输，从而影响突触功能和行为。 3) 检验减少传输增强 APP 处理的假设在神经元中。