Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks A?-Fibrinogen Interaction and A?-Induced Contact System Activation.

ABSTRACT: Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and ?-amyloid (A?), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since A? oligomers have a much stronger affinity for fibrinogen than A? monomers, we tested whether amyloid aggregation inhibitors could block the A?-fibrinogen interaction and found that some A? aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the A?-fibrinogen interaction but also retained its potency toward the A?42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated A?42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the A?-fibrinogen interaction and A? aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as A? aggregation-driven pathology in AD.

SUBMITTER: Singh PK 

PROVIDER: S-EPMC5829012 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature