title: A closer look at alpha-secretase.
abstract: Accumulation of amyloid beta-peptides (Abeta) in the brain is believed to contribute to the development of Alzheimer disease (AD). Abeta, a 40-42 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by sequential cleavages via beta- and gamma-secretases. However, the predominant route of APP processing consists of successive cleavages by alpha- and gamma-secretases. Alpha-secretase attacks APP inside the Abeta sequence, and therefore prevents formation of neurotoxic Abeta. After cleavage by alpha-secretase, the soluble N-terminal domain of APP, which possesses neurotrophic and neuroprotective properties, is released. In AD patients, a decrease in alpha-secretase processing of APP has been found and therefore, strategies to improve alpha-secretase activity are obvious. Several years after descriptive reports on alpha-secretase, the responsible enzymes have been identified to belong to the family of A Disintegrin And Metalloproteinase (ADAM). Three of these membrane-anchored zinc-dependent metalloproteinases, ADAM10 as well as ADAM17 and presumably also ADAM9 display alpha-secretase activity. Since the individual knock-out of these proteinases in neither case completely prevented alpha-secretase processing of APP, it seems likely that different ADAMs are compensating mutually, and under different conditions may contribute to alpha-secretase cleavage of APP. In addition to ADAMs, perhaps other membrane-associated metalloproteinases contribute to the shedding of APP. Stimulation of alpha-secretase activities can be achieved via several signaling cascades including phospholipase C, phosphatidylinositol 3-kinase and serine/threonine-specific kinases such as protein kinases C, and mitogen activated protein kinases. Direct activation of protein kinase C and stimulation of distinct G protein-coupled receptors are known to increase alpha-secretase processing of APP. Agonists for M1 muscarinic acetylcholine receptors and serotonin 5-HT4 receptors are currently in clinical trials to test their efficiency in the treatment of AD.
authors.affiliation: Institute of Biochemistry, Johannes Gutenberg University Mainz, Becherweg 30, 55099 Mainz, Germany. postina@uni-mainz.de
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D043562:Receptors, G-Protein-Coupled; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins