ADAMs family members as amyloid precursor protein alpha-secretases.
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.
Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom.
Tobias M J
TM
Allinson
Edward T
ET
Parkin
Anthony J
AJ
Turner
Nigel M
NM
Hooper
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000145:classification / Q000378:metabolism*; D008670:Metals / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D002800:Cholinesterase Inhibitors; D012739:Gonadal Steroid Hormones; D008670:Metals; D018721:Muscarinic Agonists; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse