Premium
The blood clotting F actor XIIIa forms unique complexes with amyloid‐beta ( A β) and colocalizes with deposited A β in cerebral amyloid angiopathy
Author(s) -
Jager M.,
Boot M. V.,
Bol J. G. J. M.,
Brevé J. J. P.,
Jongenelen C. A. M.,
Drukarch B.,
Wilhelmus M. M. M.
Publication year - 2016
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12244
Subject(s) - cerebral amyloid angiopathy , factor xiiia , chemistry , fibrin , blood–brain barrier , pathology , immunology , medicine , central nervous system , disease , dementia
Aims Cerebral amyloid angiopathy ( CAA ) is a key pathological hallmark of Alzheimer's disease ( AD ) characterized by accumulation of amyloid‐beta ( A β) protein in blood vessel walls. CAA impairs vessel functioning, affects blood brain barrier integrity and accelerates cognitive decline of AD patients. Unfortunately, mechanisms underlying A β deposition in the vessel wall remain largely unknown. F actor XIIIa ( FXIIIa ) is a blood‐derived transglutaminase crucial in blood coagulation by cross‐linking fibrin molecules. Evidence is mounting that blood‐derived factors are present in CAA and may play a role in protein deposition in the vessel wall. We therefore investigated whether FXIIIa is present in CAA and if FXIIIa cross‐link activity affects A β aggregation. Methods Using immunohistochemistry, we investigated the distribution of FXIIIa , its activator thrombin and in situ FXIIIa activity in CAA in post‐mortem AD tissue. We used surface plasmon resonance and Western blot analysis to study binding of FXIIIa to A β and the formation of FXIIIa ‐ A β complexes, respectively. In addition, we studied cytotoxicity of FXIIIa ‐ A β complexes to cerebrovascular cells. Results FXIIIa , thrombin and in situ FXIIIa activity colocalize with the A β deposition in CAA . Furthermore, FXIIIa binds to A β with a higher binding affinity for A β 1–42 compared with A β 1–40 . Moreover, highly stable FXIIIa ‐ A β complexes are formed independently of FXIIIa cross‐linking activity that protected cerebrovascular cells from A β‐induced toxicity in vitro. Conclusions Our data showed that FXIIIa colocalizes with A β in CAA and that FXIIIa forms unique protein complexes with A β that might play an important role in A β deposition and persistence in the vessel wall.