The blood clotting Factor XIIIa forms unique complexes with amyloid-beta (A[beta]) and colocalizes with deposited A[beta] in cerebral amyloid angiopathy

Aims Cerebral amyloid angiopathy (CAA) is a key pathological hallmark of Alzheimer's disease (AD) characterized by accumulation of amyloid-beta (A[beta]) 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[beta] deposition in the vessel wall remain largely unknown. Factor 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[beta] aggregation. Methods Using immunohistochemistry, we investigated the distribution of FXIIIa, its activator thrombin and in situFXIIIa activity in CAA in post-mortem AD tissue. We used surface plasmon resonance and Western blot analysis to study binding of FXIIIa to A[beta] and the formation of FXIIIa-A[beta] complexes, respectively. In addition, we studied cytotoxicity of FXIIIa-A[beta] complexes to cerebrovascular cells. Results FXIIIa, thrombin and in situFXIIIa activity colocalize with the A[beta] deposition in CAA. Furthermore, FXIIIa binds to A[beta] with a higher binding affinity for A[beta]1-42 compared with A[beta]1-40. Moreover, highly stable FXIIIa-A[beta] complexes are formed independently of FXIIIa cross-linking activity that protected cerebrovascular cells from A[beta]-induced toxicity in vitro. Conclusions Our data showed that FXIIIa colocalizes with A[beta] in CAA and that FXIIIa forms unique protein complexes with A[beta] that might play an important role in A[beta] deposition and persistence in the vessel wall.