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ACS Chem Neurosci. 2017 Sep 20;8(9):1960-1969. doi: 10.1021/acschemneuro.7b00107. Epub 2017 Jul 20.

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

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Institute of Physics, Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
Institute for Computational Science and Technology , Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
Division of Theoretical Physics, Dong Thap University , 783 Pham Huu Lau Street, Ward 6, Cao Lanh City, Dong Thap, Vietnam.
Biomedical Engineering Department, University of Technology , VNU HCM 268 Ly Thuong Kiet Street, District 10, Ho Chi Minh City, Vietnam.
Department of Theoretical Physics, University of Natural Sciences, VNU , 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Vietnam.
Department of Biophysics Institute of Experimental Physics, Slovak Academy of Sciences , Watsonova 47, 040 01 Kosice, Slovakia.


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.


Aβ fibril; Aβ oligomer; Bexarotene; amyloid beta peptide; binding free energy

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