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J Biol Chem. 2019 Jan 11;294(2):390-396. doi: 10.1074/jbc.RA118.005352. Epub 2018 Nov 8.

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

Author information

1
From the Michael Smith Laboratories, and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
2
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
3
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514.
4
Departments of Microbiology & Immunology, Medical Genetics, Zoology, and Urology, the Djavad Mowafaghian Centre for Brain Health, the Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4, and.
5
From the Michael Smith Laboratories, and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4, ckastrup@msl.ubc.ca.

Abstract

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 (k cat/Km = 1.5 × 105 m-1s-1), as well as to fibrin, platelet proteins, and blood clots under flow in vitro 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.

KEYWORDS:

Alzheimer's disease; amyloid-beta (AB); coagulation factor XIII; fibrin; neurodegeneration; oligomerization; protein aggregation; transglutaminase; vascular biology

PMID:
30409906
PMCID:
PMC6333891
[Available on 2020-01-11]
DOI:
10.1074/jbc.RA118.005352
[Indexed for MEDLINE]

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