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

  • Elżbieta Kojro
  • Falk Fahrenholz
Part of the Subcellular Biochemistry book series (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.

Key words

α-secretase non-amyloidogenic pathway Alzheimer’s disease ADAM-9 ADAM-10 ADAM-17 cholesterol G-protein-coupled receptors acetyl choline esterase inhibitors 

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Elżbieta Kojro
    • 1
  • Falk Fahrenholz
    • 1
  1. 1.Institute of BiochemistryJohannes Gutenberg UniversityMainzGermany

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