γ-Secretase modulator in Alzheimer's Disease: Shifting the end

Weiming Xia, Stephen T. Wong, Eugene Hanlon, Peter Morin

Research output: Contribution to journalReview article

32 Scopus citations

Abstract

The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat (LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the γ-secretase era. γ-Secretase modulators, by definition, only block the γ-secretase cleavage of amyloid-β protein precursor (AβPP) to generate the longer, 42-residue amyloid-β (Aβ42) without changing the production of total Aβ. The first generation GSMs were shown to block Aβ42 generation while increasing Aβ38. The non-steroidal anti-inflammatory drug, Tarenflurbil, binds to AβPP and shifts the cleavage site from Aβ42 to Aβ38. In addition, Tarenflurbil does not affect the γ-secretase cleavage of Notch. Even before the failed clinical trials of Tarenflurbil, second generation GSMs had emerged, and some of these GSMs interact with presenilin, which carries the active site of the γ-secretase. While second generation GSMs are pharmacologically superior to first generation GSMs, in vivo Aβ profiles (decreased levels of Aβ38, Aβ40, and Aβ42) in animals treated with potent GSMs are strikingly different from those in cultured cells. Thus, the unique pharmacologic properties of new GSMs and their mechanisms of action need to be elucidated in order to avoid the fate of Tarenflurbil. It is critical to understand how GSMs shift the "end" in vivo, i.e., shifting the γ-secretase cleavage at the C-terminal end of Aβ. In view of the myriad effects of candidate GSMs on Aβ production in cells and animals, drug development would benefit from better definition of the target-GSM interaction and physiological function of shorter Aβ peptides.

Original languageEnglish (US)
Pages (from-to)685-696
Number of pages12
JournalJournal of Alzheimer's Disease
Volume31
Issue number4
DOIs
StatePublished - Jan 1 2012

Keywords

  • Alzheimer's disease
  • amyloid
  • inhibitor
  • modulator
  • Notch
  • presenilin
  • secretase

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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