title: Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity.
abstract: Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by Aβ-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered β-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 Cl ion, namely Cl-NQTrp, is also an effective inhibitor of tau aggregation in vitro and in vivo. Cl-NQTrp was previously shown to efficiently inhibit the aggregation of various amyloidogenic proteins and peptides. We demonstrate that Cl-NQTrp inhibits the in vitro assembly of PHF6, the aggregation-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 Cl-NQTrp could be a unique potential therapeutic for AD since it targets aggregation of both Aβ and tau.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Interdisciplinary Sagol School of Neurosciences, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Frenkel-Pinter
authors.forename: Sharon
authors.initials: S
authors.lastname: Tal
authors.forename: Roni
authors.initials: R
authors.lastname: Scherzer-Attali
authors.forename: Malak
authors.initials: M
authors.lastname: Abu-Hussien
authors.forename: Idan
authors.initials: I
authors.lastname: Alyagor
authors.forename: Tal
authors.initials: T
authors.lastname: Eisenbaum
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D005123:Eye / Q000187:drug effects / Q000473:pathology; D009281:Naphthalenes / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D024801:Tauopathies / Q000188:drug therapy / Q000378:metabolism*; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C574895:N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-tryptophan; D009281:Naphthalenes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D016875:tau Proteins; D014364:Tryptophan