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

3 Citations (Scopus)

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

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Fibrinogen
Agglomeration
Chemical activation
Alzheimer Disease
Amyloid
Fibrinolysin
Fibrinolysis
Pathology
Coagulation
Oligomers
Cognition
Blood Vessels
2-aminopyrimidine
Proteins
Thrombosis
Blood
Monomers
Inflammation

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Singh, Pradeep K. ; Kawasaki, Masanori ; Berk-Rauch, Hanna E. ; Nishida, Goushi ; Yamasaki, Takeshi ; Foley, Michael A. ; Norris, Erin H. ; Strickland, Sidney ; Aso, Kazuyoshi ; Ahn, Hyung Jin. / Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation. In: Biochemistry. 2018 ; Vol. 57, No. 8. pp. 1399-1409.
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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.",
author = "Singh, {Pradeep K.} and Masanori Kawasaki and Berk-Rauch, {Hanna E.} and Goushi Nishida and Takeshi Yamasaki and Foley, {Michael A.} and Norris, {Erin H.} and Sidney Strickland and Kazuyoshi Aso and Ahn, {Hyung Jin}",
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Singh, PK, Kawasaki, M, Berk-Rauch, HE, Nishida, G, Yamasaki, T, Foley, MA, Norris, EH, Strickland, S, Aso, K & Ahn, HJ 2018, 'Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation', Biochemistry, vol. 57, no. 8, pp. 1399-1409. https://doi.org/10.1021/acs.biochem.7b01214

Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation. / Singh, Pradeep K.; Kawasaki, Masanori; Berk-Rauch, Hanna E.; Nishida, Goushi; Yamasaki, Takeshi; Foley, Michael A.; Norris, Erin H.; Strickland, Sidney; Aso, Kazuyoshi; Ahn, Hyung Jin.

In: Biochemistry, Vol. 57, No. 8, 27.02.2018, p. 1399-1409.

Research output: Contribution to journalArticle

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T1 - Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation

AU - Singh, Pradeep K.

AU - Kawasaki, Masanori

AU - Berk-Rauch, Hanna E.

AU - Nishida, Goushi

AU - Yamasaki, Takeshi

AU - Foley, Michael A.

AU - Norris, Erin H.

AU - Strickland, Sidney

AU - Aso, Kazuyoshi

AU - Ahn, Hyung Jin

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N2 - 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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