Abstract
There is a substantial body of evidence indicating that β-amyloid peptides (Aβ) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of Aβ through inhibition of the γ-secretase enzyme, which cleaves Aβ from the amyloid precursor protein (APP). We demonstrate here that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant γ-secretase inhibitor N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) attenuates the appearance of amyloid plaques in the Tg2576 mouse. These reductions in plaques were also accompanied by a decrease in the level of reactive gliosis. The morphometric and histological measures agreed with biochemical analysis of Aβ(40) and Aβ(42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing Aβ levels does not significantly alter deposit growth once initiated. Furthermore, we demonstrate that these beneficial effects can be achieved without causing histopathological changes in the ileum, spleen, or thymus as a consequence of blockade of the processing of alternative substrates, such as the Notch family of receptors. This indicates that in vivo a therapeutic window between these substrates seems possible—a key concern in the development of this approach to AD. An understanding of the mechanisms whereby MRK-560 shows differentiation between the APP and Notch proteolytic pathway of γ-secretase should provide the basis for the next generation of γ-secretase inhibitors.
Footnotes
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J.D.B. and D.W.S. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.114330.
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ABBREVIATIONS: AD, Alzheimer's disease; Aβ, β-amyloid peptides; APP, amyloid precursor protein; MRK-560, N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide; DEA, diethylamine; GnHCl, guanidine hydrochloride; GFAP, glial fibrillary acidic protein; LY-411575, N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide; BMS-299897, 2-[(R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid.
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↵1 Current affiliation: Department of Neuroscience, Amgen, Thousand Oaks, California.
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↵2 Current affiliation: Merck and Co. Inc., West Point, Pennsylvania.
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↵3 Current affiliation: Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, United Kingdom.
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↵4 Current affiliation: Cellzome (UK) Ltd., Little Chesterford, Cambridge, United Kingdom.
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↵5 Current affiliation: ITI Life Sciences, Dundee, Scotland, United Kingdom.
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↵6 Current affiliation: Department of Molecular Profiling, Merck Research Laboratories, Merck and Co, Inc., Rahway, New Jersey.
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↵7 Current affiliation: Department of Medicinal Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.
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↵8 Current affiliation: Johnson and Johnson, Product Research and Development, La Jolla, San Diego, California.
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↵9 Current affiliation: Research and Development, Almac Sciences, Craigavon, Northern Ireland, United Kingdom.
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↵10 Current affiliation: Neuroscience Drug Discovery Merck Research Laboratories, Boston, Massachusetts.
- Received September 20, 2006.
- Accepted November 9, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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