ADAMs family members as amyloid precursor protein alpha-secretases.

Abstract

In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-beta domain by alpha-secretase precluding deposition of intact amyloid-beta peptide. The large ectodomain released from the cell surface by the action of alpha-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that alpha-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-alpha convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of alpha-secretase. We review the evidence for each of these ADAMs acting as the alpha-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 alpha-secretase site. We also discuss how upregulation of alpha-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.

• Authors: Tobias M J Allinson, Edward T Parkin, Anthony J Turner, Nigel M Hooper
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 74 Issue 3 Pg. 342-52 (Nov 01 2003) ISSN: 0360-4012 [Print] United States
• PMID: 14598310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Amyloid beta-Protein Precursor
• Anti-Inflammatory Agents, Non-Steroidal
• Anticholesteremic Agents
• Cholinesterase Inhibitors
• Gonadal Steroid Hormones
• Metals
• Muscarinic Agonists
• Amyloid Precursor Protein Secretases
• Endopeptidases
• Aspartic Acid Endopeptidases
• BACE1 protein, human
• ADAM Proteins
• Metalloendopeptidases
• ADAM17 Protein
• ADAM17 protein, human
• Adam17 protein, mouse

Topics

• ADAM Proteins
• ADAM17 Protein
• Alzheimer Disease (metabolism)
• Amyloid Precursor Protein Secretases
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Anticholesteremic Agents (pharmacology)
• Aspartic Acid Endopeptidases
• Cholinesterase Inhibitors (pharmacology)
• Endopeptidases (metabolism)
• Gonadal Steroid Hormones (metabolism)
• Humans
• Metalloendopeptidases (classification, metabolism)
• Metals (metabolism)
• Muscarinic Agonists (pharmacology)