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

In cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the amyloid beta (A beta) 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 beta in CAA, the ability of FXIIIa to cross-link A beta has not been demonstrated. Using Western blotting, kinetic assays, and micro-fluidic analyses, we show that FXIIIa covalently cross-links A beta 40 into dimers and oligomers (k(cat)/K-m = 1.5 x 10(5) M-1 s(-1)), as well as to fibrin, platelet proteins, and blood clots under flow in vitro. A beta 40 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 beta deposits in CAA and Alzheimer's disease.