PMID- 30211407
OWN - NLM
STAT- MEDLINE
DCOM- 20190321
LR  - 20190321
IS  - 1463-9084 (Electronic)
IS  - 1463-9076 (Linking)
VI  - 20
IP  - 37
DP  - 2018 Sep 26
TI  - Bexarotene cannot reduce amyloid beta plaques through inhibition of production of 
      amyloid beta peptides: in silico and in vitro study.
PG  - 24329-24338
LID - 10.1039/c8cp00049b [doi]
AB  - Recently, it has been reported that anti-cancer drug bexarotene can remarkably 
      destroy amyloid beta (Abeta) 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 Abeta peptide. 
      Therefore, an interesting question emerges of whether bexarotene can destroy Abeta 
      plaques by direct interaction with them or by preventing production of Abeta 
      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 Abeta production through 
      bexarotene binding to beta-secretase which can cleave Abeta 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 beta-secretase. This result has been also confirmed by our in 
      vitro experiment implying that bexarotene cannot clear amyloid plaques through 
      inhibition of Abeta production. We have also shown that bexarotene tightly binds to 
      both peroxisome proliferator-activated receptor gamma (PPAR-gamma) and retinoid X 
      receptors (RXRs). Thus, our result does not contradict the hypothesis that the 
      reduction of Abeta plaques occurs due to bexarotene-induced overexpression of ApoE4.
FAU - Pham, Huy Dinh Quoc
AU  - Pham HDQ
AD  - Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 
      Warsaw, Poland. masli@ifpan.edu.pl.
FAU - Thai, Nguyen Quoc
AU  - Thai NQ
FAU - Bednarikova, Zuzana
AU  - Bednarikova Z
FAU - Linh, Huynh Quang
AU  - Linh HQ
FAU - Gazova, Zuzana
AU  - Gazova Z
FAU - Li, Mai Suan
AU  - Li MS
LA  - eng
PT  - Journal Article
PL  - England
TA  - Phys Chem Chem Phys
JT  - Physical chemistry chemical physics : PCCP
JID - 100888160
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (PPAR gamma)
RN  - 0 (Retinoid X Receptors)
RN  - A61RXM4375 (Bexarotene)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Amyloid Precursor Protein Secretases/chemistry
MH  - Amyloid beta-Peptides/*antagonists & inhibitors/chemistry
MH  - Bexarotene/*chemistry
MH  - Computer Simulation
MH  - Humans
MH  - *Models, Molecular
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - PPAR gamma/chemistry
MH  - Plaque, Amyloid/*chemistry
MH  - Protein Binding
MH  - Protein Conformation
MH  - Retinoid X Receptors/chemistry
EDAT- 2018/09/14 06:00
MHDA- 2019/03/22 06:00
CRDT- 2018/09/14 06:00
PHST- 2018/09/14 06:00 [pubmed]
PHST- 2019/03/22 06:00 [medline]
PHST- 2018/09/14 06:00 [entrez]
AID - 10.1039/c8cp00049b [doi]
PST - ppublish
SO  - Phys Chem Chem Phys. 2018 Sep 26;20(37):24329-24338. doi: 10.1039/c8cp00049b.