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

淀粉样前体蛋白(APR)是阿尔茨海默病(AD)突变的关键因素 在人类中，改变APR处理或过度表达APP似乎足以导致AD和 产生淀粉样斑块，这是阿尔茨海默病神经病理的一个恒定特征。尽管大多数人都在研究AD APP的Abeta蛋白降解片段的潜在毒性研究进展，大量观察 指出由其他APP蛋白降解产物或过度表达引起的显著神经元缺陷 完整的应用程序本身。一组一致且长期存在的观察表明，一个高度相关的 APP过量引起的表型是轴突中毒，这在AD早期和晚期也可能存在 运输机械。这种机制是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。这些观察结果也 提供一种方法，将APP行为与AD中发现的其他主要神经病理，即神经纤维联系起来 Tangles，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。因为人类突变形式的过度表达 鼠标中的APP是AD的主要模式之一，因为APP的过度表达可能就足够了 要导致某些形式的阿尔茨海默病，了解APP在神经元中过度表达的后果至关重要。 尤其是过量的APP如何毒化轴突运输。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过度表达和 Abeta的毒性是明显的。一个需要进一步评估的相关问题从我们最近的 观察到传输缺陷可能会增强APP的处理能力，可能会导致自催化螺旋 缺陷的存在。为了了解APP在神经元中过度表达的后果，特别是如何 过量的APP毒化轴突运输，并解决Abeta是否在导致轴突运输中发挥作用 我们提出的缺陷是：1)测试APP控制自己在“顺位”中的传输的假设。2)测试 假设APP或其加工产品的增加会毒化反式运输，从而影响 突触功能和行为。3)验证减少传输增强应用程序处理能力的假设 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.