Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
| Autor: | Kenneth Stockling, Johan Lundkvist, Johanna Wanngren, Susanne Rosqvist, Johan Lund, Samuel P.S. Svensson, Anna-Lena Berg, Anna Ridderstad-Wollberg, Fredrik Olsson, Lutgarde Serneels, Åsa Malmberg, Per I. Arvidsson, Bart De Strooper, Susanne Gustavsson, Hongmei Yan, Shaobo Jin, Urban Lendahl, Anders Juréus, Rebecka Klintenberg, Charlotte B. Nilsson, Santiago Parpal, Tomas Borgegard, Helena Karlström, Patrik Wollberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Sulfonamides
Amyloid beta-Peptides biology Side effect Receptors Notch Amyloid beta General Neuroscience Notch signaling pathway Brain Articles Pharmacology medicine.disease Presenilin In vitro Mice Tolerability In vivo Alzheimer Disease Presenilin-2 biology.protein medicine Animals Alzheimer's disease Amyloid Precursor Protein Secretases Signal Transduction |
| Popis: | γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD. ispartof: Journal of Neuroscience vol:32 issue:48 pages:17297-17305 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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