Coagulation factor XIIIa cross-links amyloid into dimers and oligomers and to blood proteins

Abstract

In cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), the amyloid (A) peptide deposits along the vascular lumen, leading to degeneration and dysfunction of surrounding tissues. Activated coagulation factor XIIIa (FXIIIa) covalently cross-links proteins in blood and vasculature, such as in blood clots and on the extracellular matrix. Although FXIIIa co-localizes with A in CAA, the ability of FXIIIa to cross-link A has not been demonstrated. Using Western blotting, kinetic assays, and microfluidic analyses, we show that FXIIIa covalently cross-links A40 into dimers and oligomers (kcat/Km 1.5 105 M1s1), as well as to fibrin, platelet proteins, and blood clots under flow in vitro. A40 also increased the stiffness of platelet-rich plasma clots in the presence of FXIIIa. These results suggest that FXIIIa-mediated cross-linking may contribute to the formation of A deposits in CAA and Alzheimer’s disease.