Activation of Human Platelets by Misfolded Proteins

Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 08/2007; 27(7):1657-65. DOI: 10.1161/ATVBAHA.107.143479
Source: PubMed


Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated.
We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(MAPK) (SB203580), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination).
Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid.

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    • "The mechanism by which Ab peptides trigger platelet activation is unknown. A previous study has demonstrated that aggregated Ab peptides, as other misfolded proteins, induce platelet activation through two different pathways initiated by CD36 or GPIb, respectively [7]. Shen and collaborators have demonstrated that the ability of Ab 1–40 to promote platelet activation and to potentiate the effect of weak agonists is completely conserved by the smaller Ab 25–35 peptide, a fragment of 11 amino acids corresponding to the intermembrane segment of the entire peptide [8]. "
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    FEBS letters 07/2013; 587(16). DOI:10.1016/j.febslet.2013.06.041 · 3.17 Impact Factor
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    • "In this study, we purified platelet membrane proteins for quantitative proteomics and identify potential biomarkers and pathways affected in patients with clinically diagnosed AD. In line with previous findings, many of the platelet-specific pathways that are changing are involved in platelet activation, and this is consistent with a role for Aβ peptide in activating platelets and leading to platelet aggregation [47]; moreover, APP from platelets is a major source of Aβ in circulating blood [15,100], suggesting a potential feed-forward mechanism since APP is established to be an alpha granule component [101], and its mobilization via platelet activation could lead to increased circulating Aβ. We did not sequence any APP Aβ peptide in the extracted membrane proteome, although APP was sequenced by eight peptides distributed across residues 41 to 662 in the total platelet proteome, suggesting that amyloid processing may occur in vitro during or prior to the membrane enrichment process and consistent with the presence in platelets of the full complement of secretase activities [18]. "
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    • "Meanwhile amyloid β release is totally independent of PKC activity [80] [81]. Platelet activation by amyloid-containing proteins is mediated through two independent pathways: i) one pathway signals through CD36, activation of p38MAPK/COX-1, which are intermediates in thromboxane A2 formation and GPIIb/IIIa activation and ii) the second pathway signals through the GPIbα and triggers aggregation as well as agglutination [35]. "
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