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Amyloid β peptide stimulates platelet activation through RhoA‐dependent modulation of actomyosin organization
Author(s) -
Sonkar Vijay K.,
Kulkarni Paresh P.,
Dash Debabrata
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-243691
Subject(s) - rhoa , platelet , chemistry , platelet activation , clot retraction , cerebral amyloid angiopathy , myosin light chain kinase , platelet adhesiveness , dense granule , microbiology and biotechnology , biochemistry , thrombin , phosphorylation , medicine , immunology , signal transduction , biology , platelet aggregation , dementia , disease
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). AP 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.—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