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Neurodegenerative Disorders: Loss of Function Through Gain of Function pp 129–140Cite as

The Putative Role of Presenilins in the Transmembrane Domain Cleavage of Amyloid Precursor Protein and Other Integral Membrane Proteins

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

Abstract

Missense mutations in the presenilin (PS)-1 and -2 genes are major causes of familial Alzheimer’s disease (AD), acting apparently in a dominant fashion (Levy-Lahad et al. 1995; Rogaev et al. 1995; Sherrington et al. 1995). Although the exact pathogenic mechanism underlying the disease process remains to be further elucidated, it is fairly established that almost all PS missense mutations affect the processing of the amyloid precursor protein (APP). The result is an increased secretion of the longer form of the amyloid peptide (Borchelt et al. 1996; Duff et al. 1996; Lemere et al. 1996; Tomita et al. 1997; Xia et al. 1997). This peptide constitutes the major component of the amyloid plaques in patients. Interestingly several of the PS mutations appear also to enhance the sensitivity of cells, and in particular neurons, to apoptotic stimuli (Deng et al. 1996; Guo et al. 1997; Janicki and Monteiro 1997; Vito et al. 1997; Wolozin et al. 1996). In principle both mechanisms could contribute to the pathogenesis of AD (Zhang et al. 1998). Insight into the biological functions of the PS in the cell is probably not only important for understanding the pathogenesis of the familial form of AD, but also of the sporadic form of AD. Interestingly, recent findings suggest that PS is involved in the proteolysis of the transmembrane domains of APP, Notch, APLP-1, and possibly Ire-1, and could therefore function as a molecular switch linking proteolysis to intracullular signaling (Annaert and De Strooper 1999).

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  1. B. De Strooper
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  2. A. Herreman
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  3. P. Cupers
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  4. K. Craessaerts
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  5. L. Serneels
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  6. W. Annaert
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Editors and Affiliations

  1. ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany

    Konrad Beyreuther

  2. Pour la Recherche Thérapeutique, Fondation IPSEN, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen Ph. D.

  3. Department of Pathology and The Mental Health Institute of Victoria, The University of Melbourne, 3052, Parkville, Victoria, Australia

    Colin L. Masters M. D.

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De Strooper, B., Herreman, A., Cupers, P., Craessaerts, K., Serneels, L., Annaert, W. (2001). The Putative Role of Presenilins in the Transmembrane Domain Cleavage of Amyloid Precursor Protein and Other Integral Membrane Proteins. In: Beyreuther, K., Christen, Y., Masters, C.L. (eds) Neurodegenerative Disorders: Loss of Function Through Gain of Function. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04399-8_9

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  • DOI: https://doi.org/10.1007/978-3-662-04399-8_9

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