CELLULAR FUNCTIONS OF ALZHEIMER'S DISEASE PROTEINS

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DESCRIPTION (adapted from the application): Genetic evidence has implicated three proteins, the beta-amyloid precursor protein (beta-APP) and the two homologous presenilins (PS-1 and PS-2), in the etiology of Alzheimer's disease (AD). The investigator had previously proposed based on precedents in other developmental systems, that one or more forms of beta-APP and PS-1 (or PS-2) may be components of an intercellular signaling system in normal physiology. beta-APP and PS-1 or PS-2 on the surfaces of neighboring cells would bind to one another specifically through their extra-cellular domains protruding from the cell surface membranes and generate a signal. beta-amyloid (Abeta) would be a proteolytic by-product of other events following this interaction. The present proposal is based on evidence that the PI and colleagues have shown for this proposed beta-APP: PS-mediated intercellular signaling event. Cultured cells, transiently transfected with either beta-APP, PS-1 or PS-2, were appropriately mixed, and were analyzed for protein tyrosine kinase activity, and for net protein tyrosine phosphorylation, with antibodies specific for phosphotyrosine (Ptyr). Within several minutes after mixing the beta-APP transfected cells with either the PS-1 or PS-2 transfected cells, the cell extracts showed significant transient increases in protein tyrosine kinase activity, and in Ptyr modification of protein substrates, that did not appear in controls. Furthermore, the spectrum of proteins modified by tyrosine phosphorylation differs depending on whether PS-1 or PS-2 is involved in the specific intercellular binding to beta-APP, which implies that PS-1 and PS-2 have distinct, rather than redundant, functions in normal physiology. The specific aims are to study the intercellular interactions between beta-APP and the PS, to determine the direction of signal, to identify the non-receptor tyrosine kinases that mediate it and to characterize the role of src kinases in the process.