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 hit compound so that it not only showed a strong inhibitory efficacy towards the AΒ-fibrinogen interaction but also retained its potency towards 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.
Pharmacology, Toxicology and Pharmaceutical Science
2
7%
Medicine and Dentistry
2
7%
Other
3
11%
Unknown
9
33%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 February 2018.
All research outputs
#19,854,405
of 24,395,432 outputs
Outputs from Biochemistry
#20,715
of 22,293 outputs
Outputs of similar age
#341,257
of 450,782 outputs
Outputs of similar age from Biochemistry
#135
of 192 outputs
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