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

Recently, it has been reported that anti-cancer drug bexarotene can remarkably destroy amyloid beta (Aß) 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 Aß peptide. Therefore, an interesting question emerges of whether bexarotene can destroy Aß plaques by direct interaction with them or by preventing production of Aß 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 Aß production through bexarotene binding to ß-secretase which can cleave Aß 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 ß-secretase. This result has been also confirmed by our in vitro experiment implying that bexarotene cannot clear amyloid plaques through inhibition of Aß production. We have also shown that bexarotene tightly binds to both peroxisome proliferator-activated receptor γ (PPAR-γ) and retinoid X receptors (RXRs). Thus, our result does not contradict the hypothesis that the reduction of Aß plaques occurs due to bexarotene-induced overexpression of ApoE4.