From the Michael Smith Laboratories, and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
J Biol Chem. 2019 Jan 11;294(2):390-396. doi: 10.1074/jbc.RA118.005352. Epub 2018 Nov 8.
In cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the amyloid β (Aβ) 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 Aβ in CAA, the ability of FXIIIa to cross-link Aβ has not been demonstrated. Using Western blotting, kinetic assays, and microfluidic analyses, we show that FXIIIa covalently cross-links Aβ40 into dimers and oligomers (/ = 1.5 × 10 ms), as well as to fibrin, platelet proteins, and blood clots under flow Aβ40 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 Aβ deposits in CAA and Alzheimer's disease.
在脑淀粉样血管病 (CAA) 和阿尔茨海默病 (AD) 中，淀粉样 β (Aβ) 肽沉积在血管腔中，导致周围组织的退化和功能障碍。活化的凝血因子 XIIIa (FXIIIa) 使血液和血管中的蛋白质发生共价交联，如在血栓和细胞外基质上。尽管 FXIIIa 在 CAA 中与 Aβ 共定位，但 FXIIIa 交联 Aβ 的能力尚未得到证实。通过 Western blot、动力学分析和微流分析，我们表明 FXIIIa 将 Aβ40 共价交联成二聚体和寡聚体（/ = 1.5 × 10 ms），以及交联纤维蛋白、血小板蛋白和流动状态下的血栓。Aβ40 还增加了富含血小板的血浆血栓在 FXIIIa 存在下的刚性。这些结果表明，FXIIIa 介导的交联可能有助于 CAA 和阿尔茨海默病中 Aβ 沉积的形成。
