ADAMs family members as amyloid precursor protein alpha-secretases

J Neurosci Res. 2003 Nov 1;74(3):342-52. doi: 10.1002/jnr.10737.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 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
  • Metalloendopeptidases / metabolism*
  • Metals / metabolism
  • Muscarinic Agonists / pharmacology


  • 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