The Alzheimer's amyloid precursor protein (APP) can be processed via alternative pathways. The amyloidogenic pathway, which occurs normally in both neuronal and non-neuronal cells, leads to the production of A beta which is found deposited in plaques of AD (Alzheimer's disease) patients. Stimulation of the non-amyloidogenic pathway, in which APP is cleaved within A beta, can be brought about via activation of protein kinase C or inhibition of protein phosphatase 1. These observations may represent first leads towards therapeutic strategies for AD. The current application proposes to extend these findings by addressing the following questions: 1) which isoforms of the protein kinases and phosphatases are responsible for regulating APP processing and A beta formation; 2) what are the effects of modulating net phosphorylation on APP expression and processing in the living brain; and, 3) what are the biological consequences of stimulating APP secretion via increasing net phosphorylation. Understanding the normal and pathological metabolism of APP, as well as the biological effects of regulating APP processing, could advance rational therapeutic strategies for APP. The long-term objective, and health-relatedness, of the proposal is discovering new avenues for the rational design of therapies for AD directed at altering APP processing and/or A beta accumulation. The techniques to be used include molecular biological, cell biological and biochemical techniques.
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