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Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation.
Biochemistry 2018 Februrary 28
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 β-amyloid (Aβ), 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 Aβ oligomers have a much stronger affinity for fibrinogen than Aβ monomers, we tested whether amyloid aggregation inhibitors could block the Aβ-fibrinogen interaction and found that some Aβ 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 Aβ-fibrinogen interaction but also retained its potency toward the Aβ42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated Aβ42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the Aβ-fibrinogen interaction and Aβ aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as Aβ aggregation-driven pathology in AD.
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