The structure and function of Alzheimer's gamma secretase enzyme complex

Sudarsan Krishnaswamy, Giuseppe Verdile, David Groth, Limbikani Kanyenda, Ralph N. Martins

Research output: Contribution to journalReview article

45 Citations (Scopus)

Abstract

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity.

Original languageEnglish
Pages (from-to)282-301
Number of pages20
JournalCritical Reviews in Clinical Laboratory Sciences
Volume46
Issue number5-6
DOIs
Publication statusPublished - Dec 2009
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Anterior pharynx defective homolog 1
  • Beta amyloid
  • Gamma secretase
  • Nicastrin
  • Notch receptor
  • Presenilin enhnacer-2
  • Presenilins
  • Regulated intramembrane proteolysis

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