γ-Secretase: Substrates and inhibitors

Marjorie J. Rochette, Michael Paul Murphy

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations

Abstract

The amyloid β-protein (Aβ) deposited in Alzheimer's disease (AD), the most common form of dementia in the elderly, is a secreted proteolytic product of the amyloid β-protein precursor (APP). Generation of Aβ from the APP requires two sequential proteolytic events, β-secretase cleavage to generate the amino terminus, followed by γ-secretase cleavage to generate the carboxyl terminus. Because this process is a central event in the pathogenesis of AD, γ-secretase is believed to be an excellent therapeutic target. γ-Secretase activity has been demonstrated to be membrane-associated, with the cleavage site primarily determined by the location of the substrate with respect to the membrane. It has also been shown that this unusual proteolytic activity not only occurs for APP, but also for proteins involved in morphogenic processes or cell proliferation and differentiation such as Notch and ErbB4. Thus far, all γ-secretase substrates are involved in some form of nuclear signaling. These recent findings have important implications for the development of pharmacological interventions that target γ-secretase.

Original languageEnglish
Pages (from-to)81-95
Number of pages15
JournalMolecular Neurobiology
Volume26
Issue number1
DOIs
StatePublished - Aug 2002

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Amyloid β-protein precursor
  • ErbB4
  • Notch
  • Presenilin
  • γ-secretase
  • γ-secretase inhibitors

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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