Received for publication July 23, 2007.
Revised September 21, 2007.
Accepted for publication September 24, 2007.

CHF5074, a Novel -Secretase Modulator, Reduces Brain -Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

Abstract

Some non-steroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of -secretase, the enzymatic complex responsible for the formation of -amyloid (A). CHF5074 is a new -secretase modulator, devoid of anti-cyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain A pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared to controls, CHF5074 treatment significantly reduced the area occupied by plaques as well as 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 A40 (-49.2 ± 9.2%, p=0.017) and A42 (-43.5 ± 9.7%, p=0.027) levels. In H4swe cells, CHF5074 reduced A42 and A40 secretion with an IC₅₀ of 3.6 and 18.4 µM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 ± 0.4 µM). At 5 µM, no effects were observed on Notch intracellular cleavage in HEK293swe cells. CHF5074 was well tolerated by Tg2576 mice. No abnormal findings were observed upon histopathological examination of the gastro-intestinal tract, indicating the absence of COX-related toxicity. Semi-quantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease.

Key words: COX, NSAIDs, Notch, Tg2576 Mice, beta-amyloid, gamma-secretase modulators

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