Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.

Vaccination against human beta-amyloid peptide (Ab) has been shown to remove the amyloid burden produced in transgenic mice overexpressing the mutated human amyloid precursor protein (APP) gene. For human beings, the efficiency of this therapeutic strategy has to take into account the specificities of human amyloid, especially at the early stages of 'sporadic' Alzheimer's disease (AD). Ab 40/42 were previously quantified in tissues from our well-established brain bank, including non-demented individuals with both mild amyloid and tau pathologies, hence corresponding to the earliest stages of Alzheimer pathology. Herein, we have adapted a proteomic method combined with western blotting and mass spectrometry for the characterization of insoluble Ab extracted in pure-formic acid. We demonstrated that amino-truncated Ab species represented more than 60% of all Ab species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, Ab oligomers were exclusively made of Ab-42 species, most of them being amino-truncated. Thus, our results strongly suggest that amino-truncated Ab-42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino-truncated species of Ab-42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological Ab products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans. Keywords: Alzheimer's disease, beta-amyloid peptide, proteomic, diagnostic, vaccination, physiopathology. Alzheimer's disease (AD) is a progressive dementing disorder characterized by the conjunction of two degenerative processes: tau pathology and amyloid pathology. Both degenerative processes are found in familial autosomal dominant AD and in 'sporadic' AD (non-mendelean). However, familial autosomal dominant AD due to mutations on amyloid precursor protein (APP) or presenilin genes are extremely rare ) and furthermore, less is known about the physiopathology of 'sporadic' AD.The cognitive decline that characterizes AD is well correlated to the cortical spreading of tau pathology (Delacourte et al. 1999). However, the amyloid pathology is in close relationship with the aetiology of the disease. We have recently shown a strong correlation between the amyloid pathology and the dynamic of progression of tau pathology in cortical brain areas, hence demonstrating a synergy between tau and amyloid pathologies in 'sporadic' AD Sergeant et al. 2002). It suggests overall that the amyloid pathology could trigger the spreading of tau pathology, thus leading to AD. This hypothesis is also illustrated in transgenic mouse models, in which the tau