title: Amyloid β peptide stimulates platelet activation through RhoA-dependent modulation of actomyosin organization.
abstract: Platelets contribute to 95% of circulating amyloid precursor protein in the body and have widely been employed as a "peripheral" model of neurons in Alzheimer's disease. We sought to analyze the effects of amyloid β (Aβ) on platelets and to understand the underlying molecular mechanism. The Aβ active fragment containing amino acid sequence 25-35 (Aβ(25-35); 10-20 μM) was found to induce strong aggregation of human platelets, granule release, and integrin activation, similar to that elicited by physiological agonists. Platelets exposed to Aβ(25-35) retracted fibrin clot and displayed augmented adhesion to collagen under arterial shear, reflective of a switch to prothrombotic phenotype. Exposure of platelets to Aβ peptide (20 μM) resulted in a 4.2- and 2.3-fold increase in phosphorylation of myosin light chain (MLC) and MLC phosphatase, respectively, which was reversed by Y27632, an inhibitor of Rho-associated coiled-coil protein kinase (ROCK). Aβ(25-35)-induced platelet aggregation and clot retraction were also significantly attenuated by Y27632. Consistent with these findings, Aβ(25-35) elicited a significant rise in the level of RhoA-GTP in platelets. Platelets pretreated with reverse-sequenced Aβ fragment (Aβ(35-25)) and untreated resting platelets served as controls. We conclude that Aβ induces cellular activation through RhoA-dependent modulation of actomyosin, and hence, RhoA could be a potential therapeutic target in Alzheimer's disease and cerebral amyloid angiopathy.
authors.affiliation: 2Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India. ddass@satyam.net.in.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Sonkar
authors.forename: Paresh P
authors.initials: PP
authors.lastname: Kulkarni
authors.forename: Debabrata
authors.initials: D
authors.lastname: Dash
mesh_terms: D000205:Actomyosin / Q000378:metabolism*; D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology / Q000633:toxicity; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011655:Pulmonary Embolism / Q000139:chemically induced; D011725:Pyridines / Q000494:pharmacology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D018994:Myosin Light Chains; D010446:Peptide Fragments; D011725:Pyridines; C108830:Y 27632; D000205:Actomyosin; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D020742:rhoA GTP-Binding Protein
keywords: clot retraction; mitochondrial respiration; myosin light chain; platelet adhesion; thromboembolism