Pollack Scott J, Lewis Huw
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex, UK.
Curr Opin Investig Drugs. 2005 Jan;6(1):35-47.
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.
蛋白水解酶γ-分泌酶在β-分泌酶切割淀粉样前体蛋白（β-APP）后进行切割，生成与阿尔茨海默病（AD）有因果关系的β-淀粉样肽。然而，γ-分泌酶还负责对越来越多的其他跨膜蛋白进行膜内切割，因此对γ-分泌酶的治疗性抑制也可能影响这些底物。由于干扰了这些新型γ-分泌酶底物的任何产物激活的潜在细胞信号通路，长期的这种阻断可能是有害的。此外，γ-分泌酶的抑制会导致其他β-APP代谢产物的改变，具有潜在的毒性和信号传导影响。本文综述了γ-分泌酶抑制剂这些脱靶效应的潜在后果。
