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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy

Borgegard, Tomas (author)
AstraZeneca, Sweden
Gustavsson, Susanne (author)
AstraZeneca, Sweden
Nilsson, Charlotte (author)
AstraZeneca, Sweden
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Parpal, Santiago (author)
AstraZeneca, Sweden
Klintenberg, Rebecka (author)
AstraZeneca, Sweden
Berg, Anna-Lena (author)
AstraZeneca, Sweden
Rosqvist, Susanne (author)
AstraZeneca, Sweden
Serneels, Lutgarde (author)
University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium
Svensson, Samuel (author)
Linköpings universitet,Farmakologi,Hälsouniversitetet
Olsson, Fredrik (author)
AstraZeneca, Sweden
Jin, Shaobo (author)
Karolinska Institute, Sweden
Yan, Hongmei (author)
AstraZeneca, Sweden
Wanngren, Johanna (author)
Karolinska Institute, Sweden
Jureus, Anders (author)
AstraZeneca, Sweden
Ridderstad-Wollberg, Anna (author)
AstraZeneca, Sweden
Wollberg, Patrik (author)
AstraZeneca, Sweden
Stockling, Kenneth (author)
AstraZeneca, Sweden
Karlstrom, Helena (author)
Karolinska Institute, Sweden
Malmberg, Asa (author)
AstraZeneca, Sweden
Lund, Johan (author)
AstraZeneca, Sweden
I. Arvidsson, Per (author)
AstraZeneca, Sweden Uppsala University, Sweden University of KwaZulu Natal, South Africa
De Strooper, Bart (author)
University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium
Lendahl, Urban (author)
Karolinska Institute, Sweden
Lundkvist, Johan (author)
Alzacure Fdn, Sweden AstraZeneca, Sweden Karolinska Institute, Sweden
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 (creator_code:org_t)
Society for Neuroscience, 2012
2012
English.
In: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
Related links:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
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  • gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta 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 gamma-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 A beta 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 gamma-secretase targeting strategy for AD.

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