Bexarotene cannot reduce amyloid beta plaques through inhibition of production of amyloid beta peptides: in silico and in vitro study

Physical Chemistry Chemical Physics : PCCP
Huy Dinh Quoc PhamMai Suan Li

Abstract

Recently, it has been reported that anti-cancer drug bexarotene can remarkably destroy amyloid beta (Aβ) plaques in mouse models suggesting therapeutic potential for Alzheimer's disease. However, the effect of bexarotene on clearance of plaques has not been seen in some mouse models. One of the possible mechanisms explaining this phenomenon is that bexarotene levels up expression of apolipoprotein 4 (ApoE4) leading to intracellular clearance of Aβ peptide. Therefore, an interesting question emerges of whether bexarotene can destroy Aβ plaques by direct interaction with them or by preventing production of Aβ peptides. In our previous work we have shown that bexarotene cannot clear amyloid aggregates due to their weak interaction using in silico and in vitro experiments. Here we explore the possibility of inhibiting Aβ production through bexarotene binding to β-secretase which can cleave Aβ peptides from amyloid precursor protein. Using the molecular mechanics-Poisson-Boltzmann surface area method and all-atom simulations we have shown that bexarotene has a very low binding affinity to β-secretase. This result has been also confirmed by our in vitro experiment implying that bexarotene cannot clear amyloid plaques through inhibiti...Continue Reading

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Methods Mentioned

BETA
in silico methods
FRET
Assay

Software Mentioned

Amber11
GAUSSIAN09
GaussView5
Autodock Vina
AutodockTools

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