Relevance of N-terminal residues for amyloid-beta binding to platelet integrin alpha(IIb)beta(3), integrin outside-in signaling and amyloid-beta fibril formation

摘要

A pathological hallmark of Alzheimer's disease (AD) is the aggregation of amyloid-beta peptides (A beta) into fibrils, leading to deposits in cerebral parenchyma and vessels known as cerebral amyloid angiopathy (CAA). Platelets are major players of hemostasis but are also implicated in AD. Recently we provided strong evidence for a direct contribution of platelets to AD pathology. We found that monomeric A beta 40 binds through its RHDS sequence to integrin alpha(IIb)beta(3), and promotes the formation of fibrillar A beta aggregates by the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin (CLU) from platelets. Here we investigated the molecular mechanisms of A13 binding to integrin alpha(IIb)beta(3) by using A beta 11 and A beta 16 peptides. These peptides include the RHDS binding motif important for integrin binding but lack the central hydrophobic core and the C-terminal sequence of A beta. We observed platelet adhesion to truncated N-terminal A beta 11 and A beta 16 peptides that was not mediated by integrin alpha(IIb)beta(3) . Thus, no integrin outside-in signaling and reduced CLU release was detected. Accordingly, platelet mediated A beta fibril formation was not observed. Taken together, the RHDS motif of A beta is not sufficient for A beta binding to platelet integrin alpha(IIb)beta(3) and platelet mediated A beta fibril formation but requires other recognition or binding motifs important for platelet mediated processes in CAA. Thus, increased understanding of the molecular mechanisms of A beta binding to platelet integrin alpha(IIb)beta(3) is important to understand the role of platelets in amyloid pathology.