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  • Borgegard, TomasAstraZeneca, Sweden (author)

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

  • Article/chapterEnglish2012

Publisher, publication year, extent ...

  • Society for Neuroscience,2012
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-87214
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-87214URI
  • https://doi.org/10.1523/JNEUROSCI.1451-12.2012DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

  • MEDICINE
  • MEDICIN

Added entries (persons, corporate bodies, meetings, titles ...)

  • Gustavsson, SusanneAstraZeneca, Sweden (author)
  • Nilsson, CharlotteAstraZeneca, Sweden (author)
  • Parpal, SantiagoAstraZeneca, Sweden (author)
  • Klintenberg, RebeckaAstraZeneca, Sweden (author)
  • Berg, Anna-LenaAstraZeneca, Sweden (author)
  • Rosqvist, SusanneAstraZeneca, Sweden (author)
  • Serneels, LutgardeUniversity of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium (author)
  • Svensson, SamuelLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)samsv36 (author)
  • Olsson, FredrikAstraZeneca, Sweden (author)
  • Jin, ShaoboKarolinska Institute, Sweden (author)
  • Yan, HongmeiAstraZeneca, Sweden (author)
  • Wanngren, JohannaKarolinska Institute, Sweden (author)
  • Jureus, AndersAstraZeneca, Sweden (author)
  • Ridderstad-Wollberg, AnnaAstraZeneca, Sweden (author)
  • Wollberg, PatrikAstraZeneca, Sweden (author)
  • Stockling, KennethAstraZeneca, Sweden (author)
  • Karlstrom, HelenaKarolinska Institute, Sweden (author)
  • Malmberg, AsaAstraZeneca, Sweden (author)
  • Lund, JohanAstraZeneca, Sweden (author)
  • I. Arvidsson, PerAstraZeneca, Sweden Uppsala University, Sweden University of KwaZulu Natal, South Africa (author)
  • De Strooper, BartUniversity of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium (author)
  • Lendahl, UrbanKarolinska Institute, Sweden (author)
  • Lundkvist, JohanAlzacure Fdn, Sweden AstraZeneca, Sweden Karolinska Institute, Sweden (author)
  • AstraZeneca, SwedenUniversity of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium (creator_code:org_t)

Related titles

  • In:Journal of Neuroscience: Society for Neuroscience32:48, s. 17297-173050270-64741529-2401

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