Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease.
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.
Pollack
Scott J
SJ
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex, UK. Scott_Pollack@merck.com
Lewis
Huw
H
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D008024:Ligands; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human