Amyloid β peptide stimulates platelet activation through RhoA‐dependent modulation of actomyosin organization

• Published in: The FASEB journal Vol. 28; no. 4; pp. 1819 - 1829
• Main Authors: Sonkar, Vijay K., Kulkarni, Paresh P., Dash, Debabrata
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01-04-2014
• Subjects: Actomyosin - metabolism; Adult; Alzheimer Disease - metabolism; Amides - pharmacology; Amino Acid Sequence; Amyloid beta-Peptides - pharmacology; Amyloid beta-Peptides - toxicity; Animals; Blood Platelets - drug effects; Blood Platelets - metabolism; clot retraction; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Female; Humans; Immunoblotting; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial respiration; myosin light chain; Myosin Light Chains - metabolism; Myosin-Light-Chain Phosphatase - metabolism; Oxygen Consumption - drug effects; Peptide Fragments - pharmacology; Peptide Fragments - toxicity; Platelet Activation - drug effects; platelet adhesion; Platelet Aggregation - drug effects; Pulmonary Embolism - chemically induced; Pyridines - pharmacology; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; thromboembolism; Young Adult; myosin light chain; thromboembolism; clot retraction; platelet adhesion; mitochondrial respiration
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.13-243691

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 (Aβ25–35; 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 Aβ25–35 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). AP25–35‐induced platelet aggregation and clot retraction were also significantly attenuated by Y27632. Consistent with these findings, Aβ25–35 elicited a significant rise in the level of RhoA‐GTP in platelets. Platelets pretreated with reverse‐sequenced Aβ fragment (Aβ35–25) 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.—Sonkar, V. K., Kulkarni, P. P., Dash, D. Amyloid β peptide stimulates platelet activation through RhoA‐dependent modulation of actomyosin organization. FASEB J. 28, 1819–1829 (2014). www.fasebj.org