Scherzer-Attali_2012_Neurobiol.Dis_46_663

An increasing body of evidence indicates a role for oligomers of the amyloid-beta peptide (Abeta) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of Abeta have been noted ranging from the larger Amyloid beta-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of Abeta. More recently a dodecameric form of Abeta with a 56 kDa molecular weight, denoted Abeta*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 Abeta*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 Abeta and prevents the formation of oligomers. We assessed the effect of Cl-NQTrp in vivo in transgenic flies expressing Abeta(1-42) in their nervous system. When these flies were fed with Cl-NQTrp a marked alleviation of their Abeta-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 Abeta*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 Abeta*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD.