Advanced

An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.

Habchi, Johnny; Arosio, Paolo; Perni, Michele; Costa, Ana Rita; Yagi-Utsumi, Maho; Joshi, Priyanka; Chia, Sean; Cohen, Samuel I A; Müller, Martin B D and Linse, Sara LU , et al. (2016) In Science advances 2(2).
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science advances
volume
2
issue
2
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • PMID:26933687
  • Scopus:84961154608
ISSN
2375-2548
DOI
10.1126/sciadv.1501244
language
English
LU publication?
yes
id
c635e4ee-b2f4-4303-8dea-798a42915443 (old id 8856526)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26933687?dopt=Abstract
date added to LUP
2016-03-15 11:57:54
date last changed
2016-10-13 04:28:14
@misc{c635e4ee-b2f4-4303-8dea-798a42915443,
  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.},
  author       = {Habchi, Johnny and Arosio, Paolo and Perni, Michele and Costa, Ana Rita and Yagi-Utsumi, Maho and Joshi, Priyanka and Chia, Sean and Cohen, Samuel I A and Müller, Martin B D and Linse, Sara and Nollen, Ellen A A and Dobson, Christopher M and Knowles, Tuomas P J and Vendruscolo, Michele},
  issn         = {2375-2548},
  language     = {eng},
  number       = {2},
  publisher    = {ARRAY(0x8d842a8)},
  series       = {Science advances},
  title        = {An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.},
  url          = {http://dx.doi.org/10.1126/sciadv.1501244},
  volume       = {2},
  year         = {2016},
}