Alzheimer's disease (AD) is characterized by the formation of amyloid plaques and cerebrovascular amyloid deposits, the principal component of which is about 4kDa amyloid peptide (A/beta). Alpha/beta is derived from a large transmembrane precursor, the amyloid precursor protein (APP), the physiological function of which remains to be elucidated. Thus, the long-term objectives of this part of the Program Project application are to identify the biochemical properties of APP. A complete understanding of the function of APP will be important in understanding the processes involved in amyloidogenesis and the contribution that alterations in the normal functions of APP may play in AD. Specific objectives include:
(Aims I and II) The structure, cellular distribution and metabolism of APP suggest that the protein may play a role in one or more aspects of cellular signalling. The cytoplasmic domain is conserved in each APP isoform, indicating an important function for this region of the protein. Proteins which interact with this domain will be purified using biochemical and molecular biological techniques and characterized using biochemical, immunological and structural methods, including cloning of the cDNAs for the protein(s);
Aim III) The short intracellular domain of APP appears to have no enzymatic activity. Therefore, the phosphorylation of APP is likely to regulate the interaction of the intracellular domain with one or more binding proteins. The effects of phosphorylation on the interaction of APP with identified binding proteins will be examined;
(Aim I V) Previous studies have shown that the COOH-terminal domain of APP is involved in certain aspects of APP trafficking and metabolism. We will examine the effect of the interaction of APP binding proteins on APP processing in cell models.
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