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Bexarotene cannot reduce amyloid beta plaques through inhibition of production of amyloid beta peptides:in silicoandin vitrostudy
- Source :
- Physical Chemistry Chemical Physics. 20:24329-24338
- Publication Year :
- 2018
- Publisher :
- Royal Society of Chemistry (RSC), 2018.
-
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 inhibition of Aβ 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 Aβ plaques occurs due to bexarotene-induced overexpression of ApoE4.
- Subjects :
- Models, Molecular
0301 basic medicine
Amyloid
Protein Conformation
Amyloid beta
General Physics and Astronomy
Plaque, Amyloid
Plasma protein binding
Molecular Dynamics Simulation
03 medical and health sciences
0302 clinical medicine
medicine
Amyloid precursor protein
Humans
Computer Simulation
Physical and Theoretical Chemistry
Receptor
Bexarotene
Amyloid beta-Peptides
biology
Chemistry
In vitro
Cell biology
Molecular Docking Simulation
PPAR gamma
Retinoid X Receptors
030104 developmental biology
biology.protein
Amyloid Precursor Protein Secretases
030217 neurology & neurosurgery
Intracellular
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 14639084 and 14639076
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Physical Chemistry Chemical Physics
- Accession number :
- edsair.doi.dedup.....003b56ff83fd837a30baff69eab2fcb0