title: Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy.
abstract: 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.
authors.affiliation: AstraZeneca, CNS and Pain Innovative Medicines, SE-15185 Södertälje, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Borgegård
authors.forename: Susanne
authors.initials: S
authors.lastname: Gustavsson
authors.forename: Charlotte
authors.initials: C
authors.lastname: Nilsson
authors.forename: Santiago
authors.initials: S
authors.lastname: Parpal
authors.forename: Rebecka
authors.initials: R
authors.lastname: Klintenberg
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Berg
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosqvist
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Samuel
authors.initials: S
authors.lastname: Svensson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Olsson
authors.forename: Shaobo
authors.initials: S
authors.lastname: Jin
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yan
authors.forename: Johanna
authors.initials: J
authors.lastname: Wanngren
authors.forename: Anders
authors.initials: A
authors.lastname: Jureus
authors.forename: Anna
authors.initials: A
authors.lastname: Ridderstad-Wollberg
authors.forename: Patrik
authors.initials: P
authors.lastname: Wollberg
authors.forename: Kenneth
authors.initials: K
authors.lastname: Stockling
authors.forename: Helena
authors.initials: H
authors.lastname: Karlström
authors.forename: Asa
authors.initials: A
authors.lastname: Malmberg
authors.forename: Johan
authors.initials: J
authors.lastname: Lund
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; C510791:MRK 560; D053766:Presenilin-2; D051880:Receptors, Notch; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases