Our goal is to test the hypothesis that compromised axonal transport plays a causative or contributory role in CNS neurodegeneration associated with the development of Alzheimer's Disease (AD). We propose to test our hypothesis using genetic and biochemical approaches in the mouse and extending our work to humans. Specifically we propose: 1) To test the inter-related hypotheses that overexpression of APP generally causes axonal transport defects and that further reductions in anterograde axonal (and perhaps dendritic transport) generally enhance Abeta production and amyloid plaque deposition in mouse models of Alzheimer's Disease. While we have seen genetic enhancements with a single APP transgene (Tg-APPswe), it is critical to know whether enhancement of APP processing by reductions in motor protein dose and reduction in axonal transport is a general phenomenon. 2) To test the hypothesis that reductions in retrograde axonal (and perhaps dendritic transport) will suppress Abeta production and amyloid plaque deposition in mouse models of Alzheimer's Disease. In Drosophila, we have seen striking suppression of APP-induced phenotypes by reducing dynein and dynactin expression. We wish to test whether these findings can be extended to mammals. If so, this finding could lead to future novel therapeutic opportunities for AD. 3) To extend work on transport defects in Drosophila and mouse models to humans and to ask whether pathology characteristic of alterations in axonal transport in basal forebrain cholinergic neurons occurs as an early event in the development of Alzheimer's Disease. We will test whether pathologies characteristic of transport failure, i.e., swollen axons with organelle and vesicle accumulations, that are observed in the mouse and Drosophila models exist in the early stages of Alzheimer's Disease in humans.
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