title: Naphthoquinone-tyrptophan reduces neurotoxic Aβ*56 levels and improves cognition in Alzheimer's disease animal model.
abstract: An increasing body of evidence indicates a role for oligomers of the amyloid-β peptide (Aβ) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of Aβ have been noted ranging from the larger Amyloid β-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of Aβ. More recently a dodecameric form of Aβ with a 56 kDa molecular weight, denoted Aβ*56, was shown to cause memory impairment in AD model mice. Here, we present for the first time a potential therapeutic strategy for AD that targets the early stages in the formation of neurotoxic Aβ*56 oligomers using a modified quinone-Tryptophan small molecule N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-Tryptophan (Cl-NQTrp). Using NMR spectroscopy we show that this compound binds the aromatic recognition core of Aβ and prevents the formation of oligomers. We assessed the effect of Cl-NQTrp in vivo in transgenic flies expressing Aβ(1-42) in their nervous system. When these flies were fed with Cl-NQTrp a marked alleviation of their Aβ-engendered reduced life span and defective locomotion was observed. Finally, intraperitoneal injection of Cl-NQTrp into an aggressive AD mouse model reduced the level of the Aβ*56 species in their brain and reversed their cognitive defects. Further experiments should assess whether this is a direct effect of the drug in the brain or an indirect peripheral effect. This is the first demonstration that targeted reduction of Aβ*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD.
authors.affiliation: Dept Molecular Microbiology & Biotechnology, Tel-Aviv University, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Scherzer-Attali
authors.forename: D
authors.initials: D
authors.lastname: Farfara
authors.forename: I
authors.initials: I
authors.lastname: Cooper
authors.forename: A
authors.initials: A
authors.lastname: Levin
authors.forename: T
authors.initials: T
authors.lastname: Ben-Romano
authors.forename: D
authors.initials: D
authors.lastname: Trudler
authors.forename: M
authors.initials: M
authors.lastname: Vientrov
authors.forename: R
authors.initials: R
authors.lastname: Shaltiel-Karyo
authors.forename: D E
authors.initials: DE
authors.lastname: Shalev
authors.forename: N
authors.initials: N
authors.lastname: Segev-Amzaleg
authors.forename: E
authors.initials: E
authors.lastname: Gazit
authors.forename: D
authors.initials: D
authors.lastname: Segal
authors.forename: D
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D052160:Benzothiazoles; D001812:Blood-Brain Barrier / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004330:Drosophila / Q000378:metabolism; D005456:Fluorescent Dyes; D006801:Humans; D008136:Longevity / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D009454:Neurofibrils / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D013844:Thiazoles; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; C574895:N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-tryptophan; D009281:Naphthalenes; D018696:Neuroprotective Agents; D013844:Thiazoles; C009462:thioflavin T; D014364:Tryptophan