CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.

Background and purpose: We evaluated the effects of CHF5074, a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice (hAPP) expressing the Swedish and London mutations of human amyloid precursor protein. Experimental approach: Sixty 6-month old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild type mice received standard diet. Key results: Compared to transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (-32.1±6.1%, P=0.005) and hippocampus (-41.5±5.5%, P=0.004). Number of plaques were also reduced by CHF5074 in both cortex (-27.9 ± 6.2%, P=0.007) and hippocampus (-34.1±7.3%, P=0.011). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (-53.7±9.8%, P=0.015) and hippocampus (-58.6±8.4%, P=0.031). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus (-56.8±12.7% and -53.5±11.3%, respectively) but not -amyloid burden (-18.2±10.6% and -25.2±10.1%, respectively). On the last day of the Morris water maze, transgenic controls performed significantly worse the non-transgenic animals on both the escape latency (28.0±4.3 vs 17.0±2.8 sec, P=0.017) and swimming path to reach the hidden platform (3.26±0.57 vs 1.95±0.34 meters, P=0.007). Transgenic animals of the CHF5074-treated group performed significantly better than transgenic controls on the distance traveled (2.12±0.33 meters, P=0.025). Ibuprofen-treated animals did not perform significantly better than transgenic controls. Conclusions and implications: Chronic CHF5074 treatment reduced brain -amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel -secretase modulator is a promising therapeutic agent for AD.