| Autor: |
Jager, M., Boot, M. V., Bol, J. G. J. M., Brevé, J. J. P., Jongenelen, C. A. M., Drukarch, B., Wilhelmus, M. M. M. |
| Předmět: |
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| Zdroj: |
Neuropathology & Applied Neurobiology; Apr2016, Vol. 42 Issue 3, p255-272, 18p |
| Abstrakt: |
Aims Cerebral amyloid angiopathy ( CAA) is a key pathological hallmark of Alzheimer's disease ( AD) characterized by accumulation of amyloid-beta ( Aβ) protein in blood vessel walls. CAA impairs vessel functioning, affects blood brain barrier integrity and accelerates cognitive decline of AD patients. Unfortunately, mechanisms underlying Aβ 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 Aβ 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 Aβ and the formation of FXIIIa- Aβ complexes, respectively. In addition, we studied cytotoxicity of FXIIIa- Aβ complexes to cerebrovascular cells. Results FXIIIa, thrombin and in situ FXIIIa activity colocalize with the Aβ deposition in CAA. Furthermore, FXIIIa binds to Aβ with a higher binding affinity for Aβ1-42 compared with Aβ1-40. Moreover, highly stable FXIIIa- Aβ complexes are formed independently of FXIIIa cross-linking activity that protected cerebrovascular cells from Aβ-induced toxicity in vitro. Conclusions Our data showed that FXIIIa colocalizes with Aβ in CAA and that FXIIIa forms unique protein complexes with Aβ that might play an important role in Aβ deposition and persistence in the vessel wall. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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