ArticleACS chemical neuroscience2014
Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer's β-amyloid peptides.
Article in ACS chemical neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 65 citations in OpenAlex.
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- Unsaturated Fatty Acids Are Decreased in Aβ Plaques in Alzheimer's Disease.Journal of neurochemistry · 2025Article
- Binding mechanism of full-length Aβ40 peptide to a mixed lipid bilayer.Frontiers in chemistry · 2024Article
- 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
- Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration.International journal of molecular sciences · 2022Article
- Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer's disease.Frontiers in molecular neuroscience · 2022Review
- Chemotherapy and the Risk of Alzheimer's Disease in Colorectal Cancer Survivors: Evidence From the Medicare System.JCO oncology practice · 2021Article
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- β-Amyloid Peptide: the Cell Compartment Multi-faceted Interaction in Alzheimer's Disease.Neurotoxicity research · 2020Review
- Pellucidin A promotes antinociceptive activity by peripheral mechanisms inhibiting COX-2 and NOS: In vivo and in silico study.PloS one · 2020Article
- Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts.Frontiers in cellular neuroscience · 2019Review
- Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.ACS chemical neuroscience · 2018Article
- Amyloid beta: structure, biology and structure-based therapeutic development.Acta pharmacologica Sinica · 2017Review
- Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.Scientific reports · 2016Article
- New Insights into Epigenetic and Pharmacological Regulation of Amyloid-Degrading Enzymes.Neurochemical research · 2016Article
- Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.The Yale journal of biology and medicine · 2016Review
- Comparison of the amyloid pore forming properties of rat and human Alzheimer's beta-amyloid peptide 1-42: Calcium imaging data.Data in brief · 2016Article
- A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes.Scientific reports · 2016Article
- An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.Science advances · 2016Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The anticancer drug bexarotene has been shown to restore cognitive functions in animal models of Alzheimer's disease, but its exact mechanism of action remains elusive. In the present report, we have used a combination of molecular, physicochemical, and cellular approaches to elucidate the mechanisms underlying the anti-Alzheimer properties of bexarotene in neural cells. First of all, we noticed that bexarotene shares a structural analogy with cholesterol. We showed that cholesterol and bexarotene compete for the same binding site in the C-terminal region of Alzheimer's β-amyloid peptide 1-42 (Aβ1-42). This common bexarotene/cholesterol binding domain was characterized as a linear motif encompassing amino acid residues 25-35 of Aβ1-42. Because cholesterol is involved in the oligomerization of Alzheimer's β-amyloid peptides into neurotoxic amyloid channels, we studied the capability of bexarotene to interfere with this process. We showed that nanomolar concentrations of bexarotene efficiently prevented the cholesterol-dependent increase of calcium fluxes induced by β-amyloid peptides Aβ1-42 and Aβ25-35 in SH-SY5Y cells, suggesting a direct effect of the drug on amyloid channel formation. Molecular dynamics simulations gave structural insights into the role of cholesterol in amyloid channel formation and explained the inhibitory effect of bexarotene. Because it is the first drug that can both inhibit the binding of cholesterol to β-amyloid peptides and prevent calcium-permeable amyloid pore formation in the plasma membrane of neural cells, bexarotene might be considered as the prototype of a new class of anti-Alzheimer compounds. The experimental approach developed herein can be used as a screening strategy to identify such compounds.
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