Bibliographic
1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro, but still able to reduce microglia activation in vivo. In previous studies, using AD mouse models, CHF5074 shown to prevent brain plaque deposition without affecting Notch processing. In addition, CHF5074 was found to reverse different types of memory deficits in young, plaque free mice. The beneficial effects of a subchronic CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal APP/Abeta and hyperphosphorylated tau. While these data suggest that CHF5074 reduces early cognitive deficits in transgenic mouse models of AD, there is no evidence as to its efficacy on cholinergic neuron dysfunction, which can take place along with intraneuronal Abeta accumulation, well before plaque deposition. Thus, in this study, the authors investigated the effects of an acute or subacute CHF5074 treatment on in vivo cognitive performance and on [3 H] acetylcholine (ACh) and GABA release from isolated nerve terminals (synaptosomes) obtained from 7- month-old transgenic Tg2576 mice. The behavioral and neurochemical effects of CHF5074 were compared with those induced, under the same experimental conditions, by the gamma secretase inhibitor LY450139 (semagacestat). Results showed that Vehicle-treated Tg2576 mice displayed an impairment of recognition memory compared with wild-type animals. This impairment was recovered in transgenic animals acutely treated with CHF5074 (30 mg/kg), while LY450139 (1, 3, 10 mg/kg) was ineffective. In frontal cortex synaptosomes from vehicle treated Tg2576 mice, K+ -evoked [3 H]ACh release was lower than that measured in wild-type mice. This reduction was absent in transgenic animals subacutely treated with CHF5074 (30 mg/kg daily for 8 days), while it was slightly, not significantly, amplified by LY450139 (3 mg/kg daily for 8 days). There were no differences between the groups on spontaneous [3 H] ACh release as well as spontaneous and K+ - evoked GABA release. These results suggest that CHF5074 has beneficial effects on visual memory and cortical cholinergic dysfunctions in pre-plaque Tg2576 mice. Together with previous findings, these data suggest that CHF5074 could be a possible candidate for early Alzheimer’s disease therapeutic regimens.