Expression of amyloid beta peptide in human platelets:: Pivotal role of the phospholipase Cγ2-protein kinase C pathway in platelet activation

The amyloid beta peptide (A beta), a mediator of neuronal and vascular degeneration in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy may have peripheral actions. Platelets are enriched with A beta and have been shown to enhance platelet actions. However, the detailed signaling pathways through which A beta activates platelets have not been previously explored. In this study, we examined the intra-platelet A beta distribution using a gold labeling technique and noted that A beta was predominantly localized in the cytoplasm of resting platelets. A marked increase in A beta-gold labeling in an open canalicular system was observed in collagen-activated platelets. Exogenous A beta (2-10 mu M) stimulated platelet aggregation accompanied by phospholipase C gamma 2 (PLC gamma 2) phosphorylation, phosphoinositide breakdown, and [Ca2+]i mobilization as well as protein kinase C (PKC) activation. Ro318220, an inhibitor of PKC, suppressed A beta-induced platelet aggregation, PKC activation, and [Ca2+]i mobilization in platelets, suggesting that the PLC gamma 2-PKC pathway is involved in A beta-induced platelet aggregation. In the electron spin resonance study, A beta (2 and 10 mu M) markedly triggered hydroxyl radical formation in platelets. In an in vivo study, A beta (2 mg/kg) significantly shortened the latency for inducing platelet plug formation in the mesenteric venules of mice. In conclusion, we are the first to demonstrate (1) the distribution of A beta in human platelets; and that (2) A beta activation of platelets is mediated, at least partially, by the PLC gamma 2-PKC pathway; and (3) A beta triggers thrombus formation in vivo. (C) 2008 Elsevier Ltd. All rights reserved.