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CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.
Br J Pharmacol. 2009 Mar; 156(6):982-93.BJ

Abstract

BACKGROUND AND PURPOSE

We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-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 beta-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 beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease.

Authors+Show Affiliations

Research and Development, Chiesi Farmaceutici, Via Palermo, Parma, Italy. b.imbimbo@chiesigroup.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19239474

Citation

Imbimbo, B P., et al. "CHF5074, a Novel Gamma-secretase Modulator, Attenuates Brain Beta-amyloid Pathology and Learning Deficit in a Mouse Model of Alzheimer's Disease." British Journal of Pharmacology, vol. 156, no. 6, 2009, pp. 982-93.
Imbimbo BP, Hutter-Paier B, Villetti G, et al. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009;156(6):982-93.
Imbimbo, B. P., Hutter-Paier, B., Villetti, G., Facchinetti, F., Cenacchi, V., Volta, R., Lanzillotta, A., Pizzi, M., & Windisch, M. (2009). CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. British Journal of Pharmacology, 156(6), 982-93. https://doi.org/10.1111/j.1476-5381.2008.00097.x
Imbimbo BP, et al. CHF5074, a Novel Gamma-secretase Modulator, Attenuates Brain Beta-amyloid Pathology and Learning Deficit in a Mouse Model of Alzheimer's Disease. Br J Pharmacol. 2009;156(6):982-93. PubMed PMID: 19239474.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. AU - Imbimbo,B P, AU - Hutter-Paier,B, AU - Villetti,G, AU - Facchinetti,F, AU - Cenacchi,V, AU - Volta,R, AU - Lanzillotta,A, AU - Pizzi,M, AU - Windisch,M, PY - 2009/2/26/entrez PY - 2009/2/26/pubmed PY - 2009/7/21/medline SP - 982 EP - 93 JF - British journal of pharmacology JO - Br J Pharmacol VL - 156 IS - 6 N2 - BACKGROUND AND PURPOSE: We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-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 beta-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 beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19239474/CHF5074_a_novel_gamma_secretase_modulator_attenuates_brain_beta_amyloid_pathology_and_learning_deficit_in_a_mouse_model_of_Alzheimer's_disease_ L2 - https://doi.org/10.1111/j.1476-5381.2008.00097.x DB - PRIME DP - Unbound Medicine ER -