title: An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.
abstract: The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer's disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Johnny
authors.initials: J
authors.lastname: Habchi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Perni
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Costa
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Maho
authors.initials: M
authors.lastname: Yagi-Utsumi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Priyanka
authors.identifier: 0000-0003-3419-2875
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Chia
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Samuel I A
authors.initials: SI
authors.lastname: Cohen
authors.affiliation: University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, Netherlands.
authors.forename: Martin B D
authors.initials: MB
authors.lastname: Müller
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, PO Box 124, 221 00 Lund, Sweden.
authors.forename: Sara
authors.identifier: 0000-0001-9629-7109
authors.initials: S
authors.lastname: Linse
authors.affiliation: University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, Netherlands.
authors.forename: Ellen A A
authors.initials: EA
authors.lastname: Nollen
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D023421:Models, Animal; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013764:Tetrahydronaphthalenes; C075222:amyloid beta-protein (1-42); D013654:Taurine; C001355:tramiprosate; D000077610:Bexarotene
keywords: chemical kinetics; molecular mechanisms; neurodegeneration; protein misfolding