Show simple item record

dc.contributor.author
Habchi, Johnny
dc.contributor.author
Arosio, Paolo
dc.contributor.author
Perni, Michele
dc.contributor.author
Costa, Ana Rita
dc.contributor.author
Yagi-Utsumi, Maho
dc.contributor.author
Joshi, Priyanka
dc.contributor.author
Chia, Sean
dc.contributor.author
Cohen, Samuel I.A.
dc.contributor.author
Müller, Martin B.D.
dc.contributor.author
Linse, Sara
dc.contributor.author
Nollen, Ellen A. A.
dc.contributor.author
Dobson, Christopher M.
dc.contributor.author
Knowles, Tuomas P. J.
dc.contributor.author
Vendruscolo, Michele
dc.date.accessioned
2018-12-07T10:50:37Z
dc.date.available
2017-06-12T06:18:05Z
dc.date.available
2018-12-07T10:50:37Z
dc.date.issued
2016-02-05
dc.identifier.other
10.1126/sciadv.1501244
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/116641
dc.identifier.doi
10.3929/ethz-b-000116641
dc.description.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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
AAAS
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
dc.subject
chemical kinetics
en_US
dc.subject
molecular mechanisms
en_US
dc.subject
protein misfolding
en_US
dc.subject
neurodegeneration
en_US
dc.title
An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Ab42 aggregates linked with Alzheimer’s disease
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 4.0 International
dc.date.published
2016-02-12
ethz.journal.title
Science Advances
ethz.journal.volume
2
en_US
ethz.journal.issue
2
en_US
ethz.pages.start
e1501244
en_US
ethz.size
14 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.notes
.
en_US
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02516 - Inst. f. Chemie- und Bioingenieurwiss. / Inst. Chemical and Bioengineering::09572 - Arosio, Paolo / Arosio, Paolo
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02516 - Inst. f. Chemie- und Bioingenieurwiss. / Inst. Chemical and Bioengineering::09572 - Arosio, Paolo / Arosio, Paolo
ethz.date.deposited
2017-06-12T06:24:25Z
ethz.source
ECIT
ethz.identifier.importid
imp593654694111678355
ethz.ecitpid
pub:178521
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-15T20:07:32Z
ethz.rosetta.lastUpdated
2018-12-07T10:51:01Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=An%20anticancer%20drug%20suppresses%20the%20primary%20nucleation%20reaction%20that%20initiates%20the%20production%20of%20the%20toxic%20Ab42%20aggregates%20linked%20with%&rft.jtitle=Science%20Advances&rft.date=2016-02-05&rft.volume=2&rft.issue=2&rft.spage=e1501244&rft.au=Habchi,%20Johnny&Arosio,%20Paolo&Perni,%20Michele&Costa,%20Ana%20Rita&Yagi-Utsumi,%20Maho&rft.genre=article&
 Search via SFX

Files in this item

Thumbnail

Publication type

Show simple item record