Journal
NEURODEGENERATIVE DISEASES
Volume 17, Issue 2-3, Pages 73-82Publisher
KARGER
DOI: 10.1159/000448518
Keywords
Alzheimer's disease; Tau protein; PHF6; Protein misfolding; Protein aggregation; Drosophila melanogaster; CI-NQTrp
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Funding
- Israel Science Foundation
- Alliance Family Foundation
- Helmholtz Israel Program
- Rosetrees Trust
- Israeli Ministry of Science and Technology
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Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by A13-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered 0-sheet oligomers and fibrils. Intervening in the toxic aggregation process is a promising therapeutic approach, but, to date, a disease-modifying therapy is neither available for AD nor for other tauopathies. Along these lines, we have previously demonstrated that a small naphthoquinone-tryptophan hybrid, termed NQTrp, is an effective modulator of tauopathy in vitro and in vivo. However, NQTrp is difficult to synthesize and is not very stable. Therefore, we tested whether a more stable and easier-to-synthesize modified version of NQTrp, containing a CI ion, namely CI-NQTrp, is also an effective inhibitor of tau aggregation in vitro and in vivo. CI-NQTrp was previously shown to efficiently inhibit the aggregation of various amyloidogenic proteins and peptides. We demonstrate that CINQTrp inhibits the in vitro assembly of PHF6, the aggrega- tion-prone fragment of tau, and alleviates tauopathy symptoms in a transgenic Drosophila model through the inhibition of tau aggregation-engendered toxicity. These results suggest that CI-NQTrp could be a unique potential therapeutic for AD since it targets aggregation of both AP and tau. (C) 2016 S. Karger AG, Basel
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