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The Non-Amyloidogenic Pathway: Structure and Function of α-Secretases

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Book cover Alzheimer’s Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 38))

Abstract

The amyloid cascade hypothesis is the most accepted explanation for the pathogenesis of Alzheimer’s disease (AD). APP is the precursor of the amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients. Proteolytic cleavage of APP by the α-secretase within the Aβ sequence precludes formation of amyloidogenic peptides and leads to a release of soluble APPsα which has neuroprotective properties. In several studies, a decreased amount of APPsα in the cerebrospinal fluid of AD patients has been observed. Three members of the ADAM family (a disintegrin and metalloproteinase) ADAM-10, ADAM-17 (TACE) and ADAM-9 have been proposed as α-secretases. We review the evidence for each of these enzymes acting as a physiologically relevant α-secretase. In particular, we focus on ADAM-10, which recently was shown in a transgenic mouse model for AD, to act as an α-secretase in vivo. We also discuss the pharmacological up-regulation of α-secretases as a possible therapeutic treatment for AD.

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  1. Institute of Biochemistry, Johannes Gutenberg University, Mainz, Germany

    Elżbieta Kojro & Falk Fahrenholz

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  1. Elżbieta Kojro
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  2. Falk Fahrenholz
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  1. Institute of Zoology, University of Mainz, Mainz, Germany

    J. Robin Harris

  2. Institute of Biochemistry, University of Mainz, Mainz, Germany

    Falk Fahrenholz

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Kojro, E., Fahrenholz, F. (2005). The Non-Amyloidogenic Pathway: Structure and Function of α-Secretases. In: Harris, J.R., Fahrenholz, F. (eds) Alzheimer’s Disease. Subcellular Biochemistry, vol 38. Springer, Boston, MA . https://doi.org/10.1007/0-387-23226-5_5

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