ArticleACS chemical neuroscience2018
Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Article in ACS chemical neuroscience, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 14 citations in OpenAlex.
- A Biomimetic Multiparametric Assay to Characterise Anti-Amyloid Drugs.International journal of molecular sciences · 2023Article
- Effects of Modulation of the Hedgehog and Notch Signaling Pathways on Osteoblast Differentiation Induced by Titanium with Nanotopography.Journal of functional biomaterials · 2023Article
- Interaction of the pitavastatin with model membranes.Biochemistry and biophysics reports · 2021Article
- Solid-state NMR spectroscopy.Nature reviews. Methods primers · 2021Article
- Substrate interaction inhibits γ-secretase production of amyloid-β peptides.Chemical communications (Cambridge, England) · 2020Article
- Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease.British journal of pharmacology · 2019Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-β (Aβ)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Aβ clearance mechanism. However, whether bexarotene induces removal of Aβ plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain α-helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by γ-secretase of the APP C-terminal fragment C99 to release Aβ in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major γ-secretase substrate, demonstrating that its inhibition of γ-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Aβ metabolism through multiple mechanisms.
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Registered trials
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