Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 11, Pages 4704-4715Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00482
Keywords
Cholic acid; molecular dynamics simulation; amyloid inhibitor; transmission electron microscopy; human insulin; A beta-42
Funding
- Council of Scientific and Industrial Research (CSIR), New Delhi, India
- Department of Biotechnology (DBT), New Delhi, India
- Indian Council of Medical Research (ICMR)
- CSIR [37(1676)/17/EMR II]
- UGC [F. 19-219/2018]
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Protein misfolding and its deviant self-assembly to converge into amyloid fibrils is associated with the perturbation of cellular functions and thus with debilitating neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, etc. A great deal of research has already been carried out to discover a potential amyloid inhibitor that can slow down, prevent, or remodel toxic amyloids. In the present study with the help of a combination of biophysical, imaging, and computational techniques, we investigated the mechanism of interaction of cholic acid (CA), a primary bile acid, with human insulin and A beta-42 and found CA to be effective in inhibiting amyloid formation. From ThT data, we inferred that CA encumbers amyloid fibrillation up to 90% chiefly by targeting elongation of fibrils with an insignificant effect on lag time, while in the case of A beta-42, CA stabilizes the peptide in its native state preventing its fibrillation. Strikingly upon adding initially at the secondary nucleation stage, CA also detained the progression/growth of insulin fibrils. CA is unable to prevent the conformational changes completely during fibrillation but tends to resist and maintain an alpha helical structure up to a significant extent at a primary nucleation stage while reducing the beta sheet rich content at the secondary nucleation stage. Moreover, CA treated samples exhibited reduced cytotoxicity and different morphology. Furthermore, the results obtained after molecular docking indicated that CA is interacting with insulin via hydrogen bonds. For future research, this study can be considered as preliminary research for the development of CA, a metabolite of our body, as a potential therapeutic agent against Alzheimer's disease without even stimulating the immunological responses.
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