Alzheimer's disease is associated with the accumulation of Aβ (amyloid β)-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 the present study, we investigated the effect of Aβ-peptides on human platelet signal transduction and function. We discovered that the 25–35 domain of Aβ-peptides induce an increase in platelet intracellular Ca2+ that stimulates α-granule and dense granule secretion and leads to the release of the secondary agonist ADP. Released ADP acts in an autocrine manner as a stimulant for critical signalling pathways leading to the activation of platelets. This includes the activation of the protein kinases Syk, protein kinase C, Akt and mitogen-activated protein kinases. Ca2+-dependent release of ADP is also the main component of 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 cerebrovascular dementia and suggest that Aβ-peptides can induce vascular complications of Alzheimer's disease by stimulating platelets in an intracellular Ca2+-dependent manner. Despite a marginal ADP-independent component suggested by low levels of signalling activity in the presence of apyrase or P2Y receptor inhibitors, Ca2+-dependent release of ADP by Aβ-peptides clearly plays a critical role in platelet activation. Targeting ADP signalling may therefore represent an important strategy to manage the cerebrovascular component of Alzheimer's disease.
- Alzheimer’s disease (AD)
Abbreviations: Aβ, amyloid β; AD, Alzheimer’s disease; AM, acetoxymethyl ester; APP, amyloid precursor protein; BAPTA, 1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid; ERK, extracellular-signal-regulated kinase; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; PRP, platelet-rich plasma; RGDS, Arg-Gly-Asp-Ser; ROCK, Rho-associated kinase; sAPP, soluble APP
- © The Authors Journal compilation © 2014 Biochemical Society