CHRONIC ADMINISTRATION OF CHF5074, A NOVEL GAMMA-SECRETASE MODULATOR, DOSE-DEPENDENTLY RESTORES OBJECT RECOGNITION MEMORY IN AGED ALZHEIMER’S DISEASE TRANSGENIC MICE

Background: CHF5074 is a new gamma-secretase modulator that after chronic administration has been shown to inhibit brain plaque deposition and to attenuate spatial and contextual memory deficits in adult transgenic Alzheimer’s disease (AD) mice. It is not known if the drug is still cognitively active in aged transgenic mice with massive plaque deposition. We evaluated the effects of chronic administration of CHF5074 on object recognition memory in 16-month old transgenic mice overexpressing the Swedish mutation of the human amyloid precursor protein. Methods: Six-month old transgenic female mice (n ¼ 16-27 per genotype per treatment) were treated with standard, CHF5074- (125 and 375 ppm) or DAPT-medicated diet (375 ppm) for 10 months up 16 months of age. Wild-type aged-matched littermates received vehicle, CHF5074 (375 ppm) or DAPT (375 ppm). The test consisted in two 10-min habituation sessions in an open field arena, followed 24 h later by a 10-min training session in which the animal was allowed to explore two identical objects. After a retention interval of 4 h, the animal was returned to the arena in which two objects, one familiar and one novel object were placed. The time exploring objects over 10 min was recorded and analyzed using a videotracking software. The ‘‘recognition index’’, defined as the percent time exploring the new object over the total time spent to explore, was used for statistical analysis. Data were analyzed using two-way ANOVA. Results: Compared to vehicle-treated wild-type mice, vehicle-treated transgenic animals showed a significantly lower recognition index (48.9 6 7.3% vs 64.1 6 5.0%, p ¼ 0.051). CHF5074 dose-dependently increased of the recognition index (62.265.4%, p ¼0.101 and 65.864.6%, p ¼ 0.031 after 125 ppm and 375 ppm, respectively). Compared to transgenic controls, DAPT (375 ppm) did not show significant effects on discrimination index (53.8 6 5.4%). In wild-type mice, neither CHF5074 (375 ppm) nor DAPT (375 ppm) produced significant effects on behavior compared to vehicletreated animals. Conclusions: These data show that chronic treatment with CHF5074 dose-dependently improves non-spatial memory in aged transgenic AD mice and support its development as potentially disease-modifying agent of A