1. Academic Validation
  2. Inhibition of Alzheimer's amyloid-beta aggregation in-vitro by carbenoxolone: Insight into mechanism of action

Inhibition of Alzheimer's amyloid-beta aggregation in-vitro by carbenoxolone: Insight into mechanism of action

  • Neurochem Int. 2017 Sep;108:481-493. doi: 10.1016/j.neuint.2017.06.011.
Sheetal Sharma 1 Bimla Nehru 2 Avneet Saini 3
Affiliations

Affiliations

  • 1 Department of Biophysics, Basic Medical Sciences Block II, Panjab University, Chandigarh 160014, India. Electronic address: sheetal.sh87@gmail.com.
  • 2 Department of Biophysics, Basic Medical Sciences Block II, Panjab University, Chandigarh 160014, India. Electronic address: bnehru@pu.ac.in.
  • 3 Department of Biophysics, Basic Medical Sciences Block II, Panjab University, Chandigarh 160014, India. Electronic address: avneet@pu.ac.in.
Abstract

Background: The major hallmark of Alzheimer's disease (AD) is the formation of amyloid aggregates, which are formed due to improper folding of proteins leading to the aggregation of amyloid beta (Aβ) 42 peptide. Inhibition of Aβ 42 aggregation using a drug such as carbenoxolone (Cbx), which has already been stated as neuroprotective, appears to be an effective approach against AD.

Objective: The present study was designed to investigate the anti-fibrillation activity of Cbx against the Aβ 42 aggregation.

Methods: The aggregation of Aβ 42 peptide was observed by performing in-vitro studies and the propensity of aggregation of Aβ 42 peptide was evaluated by the prediction of binding sites and amyloidogenic regions. The binding of Cbx in these binding sites was predicted by computational studies.

Results: Thioflavin-T (Th-T assay), congo red assay and circular dichroism (CD) analysis suggested significant inhibition of Aβ 42 aggregation by Cbx. The propensity of aggregation of Aβ 42 peptide was evaluated by the prediction of binding sites and amyloidogenic regions. The mechanism of anti-fibrillation activity of Cbx was elucidated by molecular docking and simulation studies and has been predicted to interact with amyloidogenic residues of Aβ 42 Peptides as well as fibrils. Cbx also interacts with residues involved in the stabilization of the oligomeric structure.

Conclusion: These results project Cbx as a suitable candidate for the inhibition of Aβ 42 aggregation and the therapeutic potential of Cbx against AD can further be studied using in-vivo experiments.

Keywords

Alzheimer's disease; Amyloid-beta 42; Anti-fibrillation; Carbenoxolone; Fibrils; Oligomers.

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