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Research & Development > Bexarotene Does Not Clear Amyloid Beta Plaques but Delays Fibril Growth: Molecular Mechanisms

Bexarotene Does Not Clear Amyloid Beta Plaques but Delays Fibril Growth: Molecular Mechanisms

On July 9th, 2017, researchers of ICST's Laboratory of Life Sciences (Nguyen Quoc Thai, Pham Dinh Quoc Huy, Mai Suan Ly) has just published the article of Bexarotene Does Not Clear Amyloid Beta Plaques but Delays Fibril Growth: Molecular Mechanisms on Journal of ACS Chemical Neuroscience.
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In 2012, it was reported that anticancer drug bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer’s like symptoms. It has been suggested that bexarotene stimulates expression of apolipoprotein E (ApoE) leading to intracellular clearance of amyloid beta (Aβ). However, the effect of bexarotene on clearance of plaques has not been seen in some mouse models. Two interesting questions include whether bexarotene can destroy Aβ fibrils via direct interaction with them and how this compound impacts the lag phase in the fibril growth process. By the Thioflavin T fluorescence assay and atomic force microscopy, we have shown that bexarotene prolongs the lag phase, but it does not degrade Aβ fibrils. The impotence of bexarotene in destroying fibrils means that this compound is weakly bound to Aβ. On the other hand, the weak binding would prevent bexarotene from prolonging the lag phase. Thus, our two main in vitro observations seem to contradict each other. In order to settle this problem at the atomic level, we have performed all-atom molecular dynamics simulations in explicit water. We have demonstrated that bexarotene is not capable to reduce amyloid deposits due to weak binding to Aβ fibrils. However, it delays the self-assembly through reduction of the β-content of Aβ monomers at high enough ligand concentrations. Bexarotene is the first compound which displays such an unusual behavior. We have also shown that bexarotene has a low binding propensity to Aβ monomer and dimer.
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Read full article here.
 
Author: Quoc Thai
Editor: Kim Loan

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