ADAMs family members as amyloid precursor protein α-secretases
Article first published online: 28 OCT 2003
Copyright © 2003 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 74, Issue 3, pages 342–352, 1 November 2003
How to Cite
Allinson, T. M.J., Parkin, E. T., Turner, A. J. and Hooper, N. M. (2003), ADAMs family members as amyloid precursor protein α-secretases. J. Neurosci. Res., 74: 342–352. doi: 10.1002/jnr.10737
- Issue published online: 28 OCT 2003
- Article first published online: 28 OCT 2003
- Manuscript Accepted: 1 MAY 2003
- Manuscript Received: 2 MAR 2003
- Medical Research Council of Great Britain
- zinc metalloproteinase
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.