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CHF5074, a novel γ‐secretase modulator, attenuates brain β‐amyloid pathology and learning deficit in a mouse model of Alzheimer's disease
Author(s) -
Imbimbo BP,
HutterPaier B,
Villetti G,
Facchinetti F,
Cenacchi V,
Volta R,
Lanzillotta A,
Pizzi M,
Windisch M
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00097.x
Subject(s) - hippocampus , microglia , genetically modified mouse , transgene , amyloid precursor protein , morris water navigation task , medicine , amyloid (mycology) , presenilin , alzheimer's disease , ibuprofen , endocrinology , inflammation , pharmacology , neuroscience , pathology , chemistry , biology , disease , biochemistry , gene
Background and purpose: We evaluated the effects of 1‐(3′,4′‐dichloro‐2‐fluoro[1,1′‐biphenyl]‐4‐yl)‐cyclopropanecarboxylic acid (CHF5074), a new γ‐secretase modulator, on brain β‐amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP). 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 with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex ( P = 0.003) and hippocampus ( P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex ( P = 0.022) and hippocampus ( P = 0.005). Plaque‐associated microglia in CHF5074‐treated animals was lower than in transgenic controls in cortex ( P = 0.008) and hippocampus ( P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not β‐amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non‐transgenic animals and the CHF5074‐treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen‐treated animals did not perform significantly better than transgenic controls. Conclusions and implications: Chronic CHF5074 treatment reduced brain β‐amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel γ‐secretase modulator is a promising therapeutic agent for Alzheimer's disease.