ABSTRACT
An increasing body of evidence indicates a role for oligomers of the amyloid-ß peptide (Aß) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of Aß have been noted ranging from the larger Amyloid ß-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of Aß. More recently a dodecameric form of Aß with a 56 kDa molecular weight, denoted Aß*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 Aß*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 Aß and prevents the formation of oligomers. We assessed the effect of Cl-NQTrp in vivo in transgenic flies expressing Aß(1-42) in their nervous system. When these flies were fed with Cl-NQTrp a marked alleviation of their Aß-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 Aß*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 Aß*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Cognition/drug effects , Naphthalenes/pharmacology , Neuroprotective Agents/pharmacology , Tryptophan/analogs & derivatives , Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Animals , Animals, Genetically Modified , Benzothiazoles , Blood-Brain Barrier/metabolism , Brain Chemistry/drug effects , Drosophila/metabolism , Fluorescent Dyes , Humans , Longevity/drug effects , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Transgenic , Microscopy, Electron, Transmission , Models, Molecular , Motor Activity/drug effects , Neurofibrils/drug effects , Neurofibrils/pathology , Psychomotor Performance/drug effects , Recognition, Psychology/drug effects , Thiazoles , Tryptophan/pharmacologyABSTRACT
OBJECTIVE: Screening strategies for gestational diabetes mellitus are controversial. Thus, we sought to determine the benefits of universal screening. PATIENTS AND METHODS: Prospective study with 2121 women involved but 1610 really screened (75.9%). According to WHO's recommendations, the strategy implemented was one-step, universal screening with a 75g oral glucose tolerance test. Screening was performed between 24 and 28 weeks of gestation or earlier if risk factors were identified. Results were compared to previous year (2001) then only a selective screening was done. RESULTS: Application of universal screening increased the prevalence of gestational diabetes mellitus (8.39% to 15.65%). Out of the 252 patients with gestational diabetes, 66 did not display any identified risk factor (26.19%). Some new risk factors have been identified: age>30, Asian, Indian or Pakistan ethnies. If these new risk factors were applied, this super selective screening would have a sensibility of 96%. DISCUSSION AND CONCLUSION: Universal screening seems to be the most appropriate routine screening strategy because it is difficult to know exactly the specific risk factors of a population to do a super selective screening.
