Amyloid precursor protein and amyloid beta 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 (Abeta), a proteolytic fragment of the amyloid precursor protein (APP). Platelets contain both APP and Abeta 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 Abeta following activation with collagen or arachidonic acid. Inhibition of platelet cyclooxygenase (COX) reduced APP but not Abeta release following those stimuli. In contrast, activation of platelets by thrombin and calcium ionophore caused release of both APP and Abeta in a COX-independent fashion. Ex vivo studies showed that, despite suppression of COX activity, administration of aspirin did not modify Abeta 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 2-phosphate and Ca(2+). 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, Abeta release may represent secretion of preformed peptide and is totally independent of both COX and PKC activity.
Skovronsky
D M
DM
Center for Experimental Therapeutics and The Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Lee
V M
VM
Praticò
D
D
D016229:Amyloid beta-Peptides / Q000097:blood*; D016564:Amyloid beta-Protein Precursor / Q000097:blood*; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D010978:Platelet Factor 4 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D011493:Protein Kinase C / Q000097:blood*; D012701:Serotonin / Q000097:blood; D013917:Thrombin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016861:Cyclooxygenase Inhibitors; D016718:Arachidonic Acid; D012701:Serotonin; D010978:Platelet Factor 4; D000001:Calcimycin; D013929:Thromboxane B2; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D013917:Thrombin; D007213:Indomethacin