Release Time:2019-03-12  Hits:

Indexed by: Journal Article

Date of Publication: 2017-01-01

Journal: ACS OMEGA

Included Journals: SCIE、PubMed

Volume: 2

Issue: 1

Page Number: 243-250

ISSN: 2470-1343

Abstract: Cardiovascular disease (CVD) and Alzheimer's disease (AD) have a mutual cause-and-effect relationship, and they share some common risk factors. Although numerous Food and Drug Administration (FDA)-approved drugs have been developed for CVD treatment, no drugs are clinically available for AD treatment. Given the common disease-causing factors and links between the two diseases and the well-demonstrated drugs for CVD, we propose to re-examine the new potential of the existing CVD drugs as amyloid-beta (A beta) inhibitors. 3-Morpholinosydnonimine hydrochloride (SIN-1) is an FDA-approved drug for inhibiting platelet aggregation in CVD. Herein, we examine the inhibition activity of SIN-1 on the aggregation and toxicity of A beta(1-42) using combined experimental and computational approaches. Collective experimental data from ThT, circular dichroism, and atomic force microscopy demonstrate that SIN-1 can effectively inhibit amyloid formation at every stage of A beta aggregation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation. The cell viability assay also shows that SIN-1 enables the protection of SH-SY5Y cells from A beta-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of A beta toward a beta-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal beta-sheet grooves of an A beta oligomer and consequently disrupts the beta-sheet structure of A beta and A beta-A beta association, explaining experimental observations. This work discovers a new function of SIN-1, making it a promising compound with dual protective roles in inhibiting both platelet and A beta aggregations against CVD and AD.