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ADAMs family members as amyloid precursor protein α-secretases

Authors

  • Tobias M.J. Allinson,

    1. Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom
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  • Edward T. Parkin,

    1. Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom
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  • Anthony J. Turner,

    1. Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom
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  • Nigel M. Hooper

    Corresponding author
    1. Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom
    • Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
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Abstract

In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-β domain by α-secretase precluding deposition of intact amyloid-β peptide. The large ectodomain released from the cell surface by the action of α-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that α-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-α convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of α-secretase. We review the evidence for each of these ADAMs acting as the α-secretase. What seems to be emerging from numerous studies, including those with mice in which each of the ADAMs has been knocked out, is that there is a team of zinc metalloproteinases able to cleave APP at the α-secretase site. We also discuss how upregulation of α-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease. © 2003 Wiley-Liss, Inc.

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