The search for γ-secretase and development of inhibitors

Jui Yi Tsai, Michael S. Wolfe, Weiming Xia

Research output: Contribution to journalReview articlepeer-review

44 Scopus citations


A considerable body of evidence has accumulated in recent years implicating the β-amyloid protein (Aβ) in the etiology of Alzheimer's disease (AD). The highly hydrophobic Aβ can nucleate and form neurotoxic fibrils that are the principal components of the cerebral plaques characteristic of AD. Aβ is formed from the amyloid-β precursor protein (APP) through two protease activities. First, β-secretase cleaves APP at the Aβ N-terminus, resulting in a soluble, secreted APP derivative (β-APPs) and a 12 kDa membrane-retained C-terminal fragment. The latter is further processed to Aβ by γ secretases, which cleave within the single transmembrane region. Other APP molecules can be cleaved by α-secretase within the Aβ region, thus precluding Aβ formation. Both β- and γ- secretase have become prime targets for the development of therapeutic agent that reduce Aβ production. β-Secretase has recently been identified as a new membrane-anchored aspartyl protease in the cathepsin D family. Inhibitor profiling, site-directed mutagenesis, and affinity labeling together have suggested that the multi-pass presenilins are γ-secretases, novel intramembrane-cleaving aspartyl proteases activated through autoproteolysis. In this article, we review the current knowledge of γ-secretase biochemistry and cell biology and the development of inhibitors of this important therapeutic target.

Original languageEnglish (US)
Pages (from-to)1087-1106
Number of pages20
JournalCurrent Medicinal Chemistry
Issue number11
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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