PT  - JOURNAL ARTICLE
AU  - Borgegård, Tomas
AU  - Gustavsson, Susanne
AU  - Nilsson, Charlotte
AU  - Parpal, Santiago
AU  - Klintenberg, Rebecka
AU  - Berg, Anna-Lena
AU  - Rosqvist, Susanne
AU  - Serneels, Lutgarde
AU  - Svensson, Samuel
AU  - Olsson, Fredrik
AU  - Jin, Shaobo
AU  - Yan, Hongmei
AU  - Wanngren, Johanna
AU  - Jureus, Anders
AU  - Ridderstad-Wollberg, Anna
AU  - Wollberg, Patrik
AU  - Stockling, Kenneth
AU  - Karlström, Helena
AU  - Malmberg, Åsa
AU  - Lund, Johan
AU  - Arvidsson, Per I.
AU  - De Strooper, Bart
AU  - Lendahl, Urban
AU  - Lundkvist, Johan
TI  - Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
AID  - 10.1523/JNEUROSCI.1451-12.2012
DP  - 2012 Nov 28
TA  - The Journal of Neuroscience
PG  - 17297--17305
VI  - 32
IP  - 48
4099  - http://www.jneurosci.org/content/32/48/17297.short
4100  - http://www.jneurosci.org/content/32/48/17297.full
SO  - J. Neurosci.2012 Nov 28; 32
AB  - 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.