An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic A beta 42 aggregates linked with Alzheimer's disease

作者:Habchi Johnny; Arosio Paolo; Perni Michele; Costa Ana Rita; Yagi Utsumi Maho; Joshi Priyanka; Chia Sean; Cohen Samuel I A; Mueller Martin B D; Linse Sara; Nollen Ellen A A; Dobson Christopher M*; Knowles Tuomas P J*; Vendruscolo Michele*
来源:Science Advances, 2016, 2(2): e1501244.
DOI:10.1126/sciadv.1501244

摘要

The conversion of the beta-amyloid (Ab) 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 A beta 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 A beta 42, the most aggregation-prone variant of A beta, 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 A beta b42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses A beta 42 deposition and its consequences in a Caenorhabditis elegans model of A beta 42-mediated toxicity. These results suggest that the prevention of the primary nucleation of A beta 42 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.

  • 出版日期2016-2