TY - JOUR
T1 - Expression of amyloid beta peptide in human platelets
T2 - Pivotal role of the phospholipase Cγ2-protein kinase C pathway in platelet activation
AU - Shen, Ming Yi
AU - Hsiao, George
AU - Fong, Tsorng Han
AU - Chou, Duen Suey
AU - Sheu, Joen Rong
N1 - Funding Information:
This work was supported by grants from the National Science Council of Taiwan (NSC92-2321-B-038-001, 93-2321-B-038-001, and 94-2321-B-038-001) and one from the Topnotch Stroke Research Center Grant, Ministry of Education, Taiwan. The authors express with gratitude to Prof. Chung Y. Hsu for his constructive comments on this study.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
KW - Amyloid β
KW - Free radicals
KW - Phospholipase C
KW - Platelet aggregation
KW - Protein kinase C
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U2 - 10.1016/j.phrs.2008.01.004
DO - 10.1016/j.phrs.2008.01.004
M3 - Article
C2 - 18313326
AN - SCOPUS:40149104924
SN - 1043-6618
VL - 57
SP - 151
EP - 158
JO - Pharmacological Research
JF - Pharmacological Research
IS - 2
ER -