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

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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.