Amyloid precursor protein and amyloid β peptide in human platelets -: Role of cyclooxygenase and protein kinase C

The main component of Alzheimer's disease (AD) senile plaques is amyloid-beta peptide (A beta), a proteolytic fragment of the amyloid precursor protein (APP), Platelets contain both APP and A beta and may contribute to the perivascular amyloid deposition seen in AD. However, no data are available concerning the biochemical mechanism(s) involved in their formation and release by these cells. We found that human platelets released APP and A beta following activation with collagen or arachidonic acid. Inhibition of platelet cyclooxygenase (COX) reduced APP but not A beta release following those stimuli. In contrast, activation of platelets by thrombin and calcium ionophore caused release of both APP and A beta in a COX-independent fashion. Ex vivo studies showed that, despite suppression of COX activity, administration of aspirin did not modify A beta or APP levels in serum or plasma, suggesting that this enzyme plays only a minor role in vivo, We examined the regulation of APP cleavage and release from activated platelets and found that cleavage requires protein kinase C (PKC) activity and is regulated by the intracellular second messengers phosphatidylinositol S-phosphate and Ca2+. Our data provide the first evidence that in human platelets COX is a minor component of APP secretion whereas PKC plays a major role in the secretory cleavage of APP. By contrast, A beta release may represent secretion of preformed peptide and is totally independent of both COX and PKC activity.