Investigator: Joseph DeGiorgis, Providence College

Mentor: Thomas Reese, National Institutes of Health

Scientific Theme: Neuroscience

Abstract: The amyloid precursor protein (APP) is a causitive agent in the pathogenesis of Alzheimer’s disease. This protein contains a single transmembrane domain and associates with membrane-bound organelles. Recently, we have shown that APP clusters on the surfaces of organelles in the squid gaint axon at a focal point between the organelles and cellular microtubules. Interestingly, it has been proposed that APP may serve as a “trailer-hitch” linking the motor protein kinesin to its intercellular cargo. While our results are in agreement with these findings, to date there is no direct evidence that APP and kinesin bind to each other in a direct or even indirect manner. However, the localization of APP to the junction between organelles and microtubules suggests that APP, like the AD protein Toa, has a microtubulebased function. Here, we setout to determine the molecular anatomy of APP organelles in order to more accurately define that organelles in association with APP and to begin to address the issue of kinesin and APP interaction. We hope to determine the concentration of APP in total axoplasm as well as in axoplasmic organelle isolates. Through biochemical purifiecation of kinesin motors we hope to determine whether APP co-purifies with motor proteins to test the trailer-hitch hypothesis. Finally, we propose to investigate the distribution of APP at the ultrastructural electron microscopy level to determine the subcellular distribution of APP at the vertebrate synapse and then to determine whther APP distribution is altered during neuronal stimulation.

Human Health Relevance: The amyloid precursor protein is a lead cause of Alzheimer’s disease as mutations in the APP gene lead to heritable forms of the disorder and a fragment of APP builds up in lesions of all AD patients. Here, we address the function of wild-type APP in hope of shedding light on its role in the pathogenesis of disease.