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

淀粉样蛋白前体蛋白（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加工或过表达APP似乎足以引起AD， 产生淀粉样斑块，这是AD神经病理学的恒定特征。虽然大多数工作在AD 发展的重点是APP的Abeta蛋白水解片段的潜在毒性，许多观察 指出由其他APP蛋白水解加工产物或过度表达引起的显著神经元缺陷 完整的APP本身。一系列长期一致的观察结果表明， 在早期和晚期AD中也可发现由过量APP引起的表型是轴突毒性， 运输机械这种机制是需要为远程神经营养信号和供应 维持功能性突触所需的蛋白质和细胞器。这些意见还 提供了一种将APP行为与AD中发现的其他主要神经病理学联系起来的方法， 缠结，由微管结合蛋白tau组成，它也参与控制 APP和其他囊泡和细胞器的运输。因为人类基因突变体的过度表达 小鼠中的APP是AD的主要模型之一，并且由于APP的过表达可能足以 要引起某些形式的AD，关键是要了解APP在神经元中过度表达的后果， 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 在轴突运输缺陷中起作用，以及APP过表达产生的缺陷和 Abeta毒性是不同的。一个需要进一步评估的相关问题出现在我们最近的 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APP在神经元中过度表达的后果，特别是如何 过量的APP毒害轴突运输，并解决Abeta是否在引起轴突运输中起作用 我们提出的缺陷：1）为了检验APP以“顺式”控制其自身运输的假设。2)测试 一种假设，即APP或其加工产物的增加会毒害反式转运， 突触功能和行为。3)为了检验减少转运增强APP加工的假设， 在神经元中。

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.