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Intracellular Traffic and Neurodegenerative Disorders pp 11–26Cite as

Intramembrane Proteolysis by γ-Secretase and Signal Peptide Peptidases

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Part of the book series: Research and Perspectives in Alzheimer's Disease ((ALZHEIMER))

Abstract

The amyloid cascade hypothesis describes a series of cumulative events that are initiated by amyloid β-peptide and finally lead to synapse and neuron loss. Obviously, the proteases involved in amyloid β-peptide generation are targets for therapeutic treatment strategies. For the development of a safe therapeutic intervention, however, we must understand the precise physiological functions and the cellular mechanisms involved in substrate recognition, selection and cleavage. Moreover, homologous proteases, whose physiological function could be affected by inhibitors, need to be discovered and assays must be developed to help determine the cross-reactive potential of such inhibitors. Here we will focus on the intramembrane cleavage of the β-amyloid precursor protein, which is performed by the γ-secretase complex. In parallel, the cellular and biochemical properties of other proteases belonging to the same family of GxGD-type aspartyl proteases, the signal peptide peptidase and their homologues, will be described. We present a common, multiple intramembrane cleavage mechanism performed by these proteases and evidence that Alzheimer's disease-associated mutations lead to a partial loss of intramembrane proteolysis.

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Authors and Affiliations

  1. Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig-Maximilians-University, Munich, 80336, Germany

    Regina Fluhrer & Christian Haass

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  1. Regina Fluhrer
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  2. Christian Haass
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Editors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Tranz Neuroscience Bldg., Toronto, ON, M5S 3H2, Canada

    Peter H. St. George-Hyslop

  2. Department of Neurology, Standford University School of Medicine, Standford, CA, 94305-5316, USA

    William C. C. Mobley

  3. Fondation IPSEN Pour la Recherche Thérapeutique, 65, quai Georges Gorse, Boulogne Billancourt, 92650, Cedex - France

    Yves Christen

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Fluhrer, R., Haass, C. (2009). Intramembrane Proteolysis by γ-Secretase and Signal Peptide Peptidases. In: George-Hyslop, P.H.S., Mobley, W.C., Christen, Y. (eds) Intracellular Traffic and Neurodegenerative Disorders. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-87941-1_2

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