The aim of this study is to determine the effects of chronic treatment with CHF5074, a novel gamma secretase modulator, on brain Abeta levels, and beta amyloid plaque deposition in the Tg2576 mouse model of AD. In addition, the authors examined peripheral Tg mouse tissue for signs of toxicity, in particular those that may be related to COX inhibition or altered Notch signaling.Twenty-eight Tg mice of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (52.2 5.6%, p = 0.0003 and 48.9 6.6%, p = 0.0004, respectively) and hippocampus (76.7 6.4%, p= 0.004 and 66.2 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (49.2 9.2%, p = 0.017) and Abeta42 (43.5 9.7%, p= 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta 42 and Abeta 40 secretion, with an IC50 of 3.6 and 18.4 uM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 uM). At 5 uM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No deaths occurred during the 17-week treatment period; body weight and body weight gain over time were very similar to those of the vehicle-treated group. At week 17, macroscopic and histological examinations of potential peripheral target organs did not show significant abnormalities. In the ileum, there were no differences in goblet cell numbers and distribution between the vehicle-dosed animals and the animals receiving CHF5074. The spleen of the CHF5074-treated animals did not show histological abnormalities. Finally, histological evaluation of other portions of the gastrointestinal tract revealed no abnormalities. Overall, the data demonstrate that chronic treatment with CHF5074 can significantly reduce the induction of amyloid deposits in the brains of Tg2576 mice without causing histopathological changes in peripheral organs that would be associated with inhibition of Notch processing by gamma secretase.