Cellular and Molecular Life Sciences

, Volume 66, Issue 9, pp 1534–1555 | Cite as

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

  • J. V. McCarthy
  • C. Twomey
  • P. Wujek


Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with an emphasis on the functional role of presenilins in cell biology.


Presenilin γ-secretase complexes regulated intramembrane proteolysis signal transduction Alzheimer’s disease 


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Copyright information

© Birkhäuser Verlag, Basel 2009

Authors and Affiliations

  1. 1.Signal Transduction Laboratory, Biochemistry DepartmentUniversity College CorkCorkIreland

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