Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation

Pradeep K. Singh, Masanori Kawasaki, Hanna E. Berk-Rauch, Goushi Nishida, Takeshi Yamasaki, Michael A. Foley, Erin H. Norris, Sidney Strickland, Kazuyoshi Aso, Hyung Jin Ahn

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)1399-1409
Number of pages11
JournalBiochemistry
Volume57
Issue number8
DOIs
StatePublished - Feb 27 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry

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    Singh, P. K., Kawasaki, M., Berk-Rauch, H. E., Nishida, G., Yamasaki, T., Foley, M. A., Norris, E. H., Strickland, S., Aso, K., & Ahn, H. J. (2018). Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation. Biochemistry, 57(8), 1399-1409. https://doi.org/10.1021/acs.biochem.7b01214