Naphthoquinone-tyrptophan reduces neurotoxic A?*56 levels and improves cognition in Alzheimer's disease animal model
Language: 
English
Abstract: 

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

Author(s): 
Scherzer-Attali, R.
Farfara, D.
Cooper, I.
Levin, A.
Ben-Romano, T.
Trudler, D.
Vientrov, M.
Shaltiel-Karyo, R.
Shalev, D. E.
Segev-Amzaleg, N.
Gazit, E.
Segal, D.
Frenkel, D.
Item Type: 
Journal Article
Publication Title: 
Neurobiology of Disease
Journal Abbreviation: 
Neurobiol. Dis.
Publication Date: 
2012-06
Publication Year: 
2012
Pages: 
663-672
Volume: 
46
Issue: 
3
ISSN: 
1095-953X
DOI: 
10.1016/j.nbd.2012.03.005
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 22449754

Turabian/Chicago Citation

R. Scherzer-Attali, D. Farfara, I. Cooper, A. Levin, T. Ben-Romano, D. Trudler, M. Vientrov, R. Shaltiel-Karyo, D. E. Shalev, N. Segev-Amzaleg, E. Gazit, D. Segal and D. Frenkel. 2012-06. "Naphthoquinone-tyrptophan reduces neurotoxic A?*56 levels and improves cognition in Alzheimer's disease animal model." Neurobiology of Disease 46: 3: 663-672. 10.1016/j.nbd.2012.03.005.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1016/j.nbd.2012.03.005 | issn = 1095-953X | volume = 46 | pages = 663-672 | last = Scherzer-Attali | first = R. | coauthors = Farfara, D., Cooper, I., Levin, A., Ben-Romano, T., Trudler, D., Vientrov, M., Shaltiel-Karyo, R., Shalev, D. E., Segev-Amzaleg, N., Gazit, E., Segal, D., Frenkel, D. | title = Naphthoquinone-tyrptophan reduces neurotoxic A?*56 levels and improves cognition in Alzheimer's disease animal model | journal = Neurobiology of Disease | date = 2012-06 | pmid = | pmc = }} </ref>