Protein phosphorylation regulates secretion of Alzheimer β/A4 amyloid precursor protein

Extracellular deposition of the β/ A4 amyloid peptide is a characteristic feature of the brain in patients with Alzheimer disease. β/A4 amyloid is derived from the amyloid precurrsor protein (APP), an integral membrane protein that exists as three major isoforms (APP₆₉₅, APP₇₅₁, and APP₇₇₀). Serreted forms of APP found in blood plasma and cerebrospinal fluid arise by proteolytic cleavage of APP within the β/A4 amyloid domain, precluding the possibility of amyloidogenesis for that population of molecules. In the present study, we have demonstrated that treatment of PC12 cells with phorbol ester produces a severalfold increase in secretion of APP₆₉₅, APP₇₅₁, and APP₇₇₀. This increase is augmented by simultaneous treatment with the protein phosphatase inhibitor okadaic acid. These data indicate that protein phosphorylation regulates intra-β amyloid cleavage and APP secretion. These and other results suggest that APP molecules can normally follow either of two processing pathways: regulated secretion or proteolytic degradation unassociated with secretion.