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

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Abstract

The amyloid β peptide (Aβ), 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 Aβ and have been shown to enhance platelet actions. However, the detailed signaling pathways through which Aβ activates platelets have not been previously explored. In this study, we examined the intra-platelet Aβ distribution using a gold labeling technique and noted that Aβ was predominantly localized in the cytoplasm of resting platelets. A marked increase in Aβ-gold labeling in an open canalicular system was observed in collagen-activated platelets. Exogenous Aβ (2-10 μM) stimulated platelet aggregation accompanied by phospholipase Cγ2 (PLCγ2) phosphorylation, phosphoinositide breakdown, and [Ca2+]i mobilization as well as protein kinase C (PKC) activation. Ro318220, an inhibitor of PKC, suppressed Aβ-induced platelet aggregation, PKC activation, and [Ca2+]i mobilization in platelets, suggesting that the PLCγ2-PKC pathway is involved in Aβ-induced platelet aggregation. In the electron spin resonance study, Aβ (2 and 10 μM) markedly triggered hydroxyl radical formation in platelets. In an in vivo study, Aβ (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 Aβ in human platelets; and that (2) Aβ activation of platelets is mediated, at least partially, by the PLCγ2-PKC pathway; and (3) Aβ triggers thrombus formation in vivo.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalPharmacological Research
Volume57
Issue number2
DOIs
Publication statusPublished - Feb 2008

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Keywords

  • Amyloid β
  • Free radicals
  • Phospholipase C
  • Platelet aggregation
  • Protein kinase C

ASJC Scopus subject areas

  • Pharmacology

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