Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release.
SCIENCE SIGNALING(2016)
Abstract
Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-beta (A beta) in the walls of cerebral vessels. CAA and A beta deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular A beta deposits, to CAA. We found that synthetic monomeric A beta 40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin alpha(IIb)beta(3), 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 A beta aggregates, and ADP acted through its receptors P2Y(1) and P2Y(12) on platelets to enhance integrin aIIbb3 activation, further increasing the secretion of clusterin and A beta 40 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 A beta-induced clusterin release and platelet-induced A beta aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited A beta aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of A beta aggregates and that A beta, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.
MoreTranslated text
Key words
integrin,platelets,cerebral vessels,clusterin
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined