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Intramembrane-Cleaving Proteases (I-CLiPs) pp 89–109Cite as

γ-Secretase And Alzheimer’S Disease

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Part of the book series: Proteases in Biology and Disease ((PBAD,volume 6))

Abstract

Deposition of the amyloid β-protein is a defining pathological characteristic of Alzheimer’s disease, and this small protein is proteolytically produced from the amyloid β-protein precursor. ,-Secretase is responsible for the second cut, which forms the C-terminus of amyloid-β and determines how much of the transmembrane domain is included in this aggregation-prone protein. This intramembrane aspartyl protease is a complex of four different integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. During assembly and maturation of the protease complex, presenilin is endoproteolyzed into two subunits, each of which contributes one aspartate to the active site. A model of successive proteolysis may explain how Alzheimer-causing mutations in presenilin can both decrease enzyme activity and increase the proportion of longer, more aggregation-prone forms of amyloid-β. Substrate apparently interacts with an initial docking site before passing in whole or in part between the two presenilin subunits to the internal water-containing active site. The ectodomain of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Inhibitors and allosteric modulators of γ-secretase activity are under investigation as potential Alzheimer therapeutics. Elucidation of detailed structural features of γ-secretase is the next logical step toward understanding how this enzyme carries out intramembrane proteolysis and will set the stage for structure-based drug design

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  1. Center For Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

    Michael S. Wolfe

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  1. University of Leeds, Leeds, United Kingdom

    Nigel M. Hooper

  2. Otto-von-Guericke Universität, Magdeburg, Germany

    Uwe Lendeckel

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Wolfe, M.S. (2007). γ-Secretase And Alzheimer’S Disease. In: Hooper, N.M., Lendeckel, U. (eds) Intramembrane-Cleaving Proteases (I-CLiPs). Proteases in Biology and Disease, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6311-4_6

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