Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-b (Ab) in the walls of cerebral vessels. CAA and Ab deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD).We investigated the contribution of platelets, which accumulate at vascular Ab deposits, to CAA. We found that synthetic monomeric Ab40 bound through its RHDS (Arg- His-Asp-Ser) sequence to integrin aIIbb3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Ab aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin aIIbb3 activation, further increasing the secretion of clusterin and Ab40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional aIIbb3, indicated that the abundance of this integrin dictated Ab-induced clusterin release and platelet-induced Ab aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Ab aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence ofCAA.Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Ab aggregates and that Ab, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.
Platelets contribute to amyloid-b aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release / Donner, L; Fälker, K; Gremer, L; Klinker, S; Pagani, G; Ljungberg, Lu; Lothmann, K; Rizzi, F; Schaller, M; Gohlke, H; Willbold, D; Grenegard, M; Elvers, M.. - In: SCIENCE SIGNALING. - ISSN 1937-9145. - 9:429(2016), pp. ra52-ra52. [10.1126/scisignal.aaf6240]
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