Biochemical and structural analysis of the interaction between beta-amyloid and fibrinogen

摘要

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 beta-amyloid (A beta), 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 A beta-fibrinogen interaction. We identified the central region of A beta 42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of A beta and by naturally occurring p3 peptides, A beta 17-40 and A beta 17-42. X-ray crystallographic analysis revealed that A beta 42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen beta-chain (beta 384-393). Furthermore, we identified an additional A beta-binding site within the alpha C region of fibrinogen. A beta binding to this alpha C 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 A beta-fibrinogen interaction and clarifies the mechanism by which A beta-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the A beta-fibrinogen interaction to treat cerebrovascular abnormalities in AD.