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Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau.

The mutagenicities of mainstream cigarette smoke (CS), a cigarette smoke condensate (CSC) and smokers' urines were investigated by using batteries of Salmonella typhimurium and Escherichia coli strains. The S9-mediated mutagenicity of CSC was remarkably enhanced when using nitroreductase- and especially O-acetyltransferase-overproducing derivatives of the classical strains TA98 and TA100, with the following rank of sensitivity: YG1024 > YG1029 > YG1021 > TA98NR > YG1026 > TA98 > TA100 > TA100-DNP6 > TA100NR > TA98-1,8-DNP6. With YG1024, a doubling of spontaneous revertants was observed with as little as 1/110 of the smoke condensate recovered from one cigarette under our experimental conditions. Similarly, the S9-mediated mutagenicity of mainstream CS was considerably increased in YG1024 and YG1029, the O-acetyltransferase-overproducing derivatives of TA98 and TA100, respectively. In the absence of S9 mix, the concentrates of 23 urine specimens from five smokers failed to revert S. typhimurium TA98 and YG1024, and were equitoxic in E. coli WP2 and its repair-deficient counterpart CM871 (uvrA-, recA-, lexA-). In the presence of S9 mix, all specimens were mutagenic, with an average YG1024:TA98 ratio of 6.6:1. These patterns suggest that the bacterial mutagenicity of smoke-associated complex mixtures is mainly due to aromatic amines. The mutagenicities of other typical constituents of CS, i.e. the polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) and the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were not appreciably enhanced in the O-acetyltransferase-overproducing strain YG1029, compared to its parental strain TA100. Moreover, BP and NNK induced less than additive mutagenic responses when combined at high doses.(ABSTRACT TRUNCATED AT 250 WORDS)