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Review
. 2005 Jan;6(1):35-47.

Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease

Scott J Pollack  1 , Huw Lewis
Affiliations
  • PMID: 15675602
Review

Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease

Scott J Pollack et al. Curr Opin Investig Drugs. 2005 Jan.

Abstract

The proteolytic enzyme gamma-secretase cleaves amyloid precursor protein (beta-APP), following beta-secretase cleavage to generate the amyloid-beta peptides that are causally linked to Alzheimer's disease (AD). However, gamma-secretase is also responsible for intramembranous cleavage of a growing list of additional transmembrane proteins, and therefore therapeutic inhibition of gamma-secretase might also affect these substrates. Such blockade over a chronic period may be deleterious, due to interference with potential cell signaling pathways activated by any of the products of these novel gamma-secretase substrates. In addition, inhibition of gamma-secretase leads to alterations in other beta-APP metabolites, with potential toxicity and signaling implications. The potential consequences of these off-target effects of gamma-secretase inhibitors are reviewed.

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