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.
Allinson
Tobias M J
TM
Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom.
Parkin
Edward T
ET
Turner
Anthony J
AJ
Hooper
Nigel M
NM
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