Amyloid peptide activates platelets through ADP release

Alzheimer’s disease is a highly debilitating disease of the central nervous system associated with the accumulation of amyloid β (Aβ) peptides in the brain. Besides their cytotoxic effect on neurons, Aβ peptides are thought to be responsible for the atherothrombotic complications associated with Alzheimer’s disease, which are collectively known as cerebrovascular disease. In this study, we have investigated the effect of Aβ peptides on human platelet signal transduction and function. Using live cell Ca 2+ spectrofluorimetry, we discovered that Aβ peptides induce an increase in platelet intracellular Ca 2+ similar to physiological agonists. This increase of intracellular Ca 2+ stimulates and dense granules secretion and leads to the release of the secondary agonist ADP. Released ADP acts in an autocrine manner as a stimulant for critical signaling pathways leading to the activation of platelets, which include the activation of the protein kinases Syk, protein kinase C, Akt, and mitogen-activated protein kinases. Ca 2+ dependent release of ADP is also responsible for the activation of the small GTPase Rap1b and the fibrinogen receptor integrin αIIbβ3, which leads to increased platelet aggregation and increased thrombus formation in human whole blood. Our discoveries complement existing understanding of the role of Aβ peptides in cerebrovascular dementia and suggest the inhibition of ADP signaling as a potential therapeutic avenue in the treatment of Alzheimer’s disease.