RESUMEN
The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with ß-amyloid (Aß), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Aß-fibrinogen interaction. We identified the central region of Aß42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Aß and by naturally occurring p3 peptides, Aß17-40 and Aß17-42. X-ray crystallographic analysis revealed that Aß42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen ß-chain (ß384-393). Furthermore, we identified an additional Aß-binding site within the αC region of fibrinogen. Aß binding to this αC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Aß-fibrinogen interaction and clarifies the mechanism by which Aß-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Aß-fibrinogen interaction to treat cerebrovascular abnormalities in AD.
