The secretases: Enzymes with therapeutic potential in Alzheimer disease

Bart De Strooper*, Robert Vassar, Todd Golde

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

536 Scopus citations

Abstract

The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor proteinα-secretase, Β-secretase and γ-secretaseare of particular interest as they are central to the generation and modulation of amyloid-Β peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions.

Original languageEnglish (US)
Pages (from-to)99-107
Number of pages9
JournalNature Reviews Neurology
Volume6
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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