期刊
NEUROBIOLOGY OF DISEASE
卷 46, 期 3, 页码 663-672出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2012.03.005
关键词
Alzheimer's disease; Abeta; AD mouse model; Oligomers; Therapy; AD fly model
资金
- Alzheimer's Association [NIRG-11-205535]
- Israeli Ministry of Health
An increasing body of evidence indicates a role for oligomers of the amyloid-beta peptide (A beta) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of A beta have been noted ranging from the larger Amyloidp-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of A beta. More recently a dodecameric form of A beta with a 56 kDa molecular weight, denoted A beta*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 A beta*56 oligomers using a modified quinone-Tryptophan small molecule N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-Tryptophan (CI-NQTrp). Using NMR spectroscopy we show that this compound binds the aromatic recognition core of A beta and prevents the formation of oligomers. We assessed the effect of CI-NQTrp in vivo in transgenic flies expressing A beta(1-42) in their nervous system. When these flies were fed with CI-NQTrp a marked alleviation of their A beta-engendered reduced life span and defective locomotion was observed. Finally, intraperitoneal injection of CI-NQTrp into an aggressive AD mouse model reduced the level of the A beta*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 A beta*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD. (C) 2012 Elsevier Inc. All rights reserved.
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