The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease.
In the nonamyloidogenic processing pathway the Alzheimer s amyloid precursor protein (APP) is proteolytically cleaved by alpha-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid beta domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPP(alpha)) released by the action of alpha-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that alpha-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of alpha-secretase. APP is constitutively cleaved by alpha-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the alpha-secretase cleavage of APP is up-regulated. The constitutive alpha-secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi. The beneficial action of cholinesterase inhibitors may in part be due to activation of muscarinic receptors, resulting in an up-regulation of alpha-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the alpha-secretase cleavage of APP both precludes the deposition of the amyloid beta peptide and releases the neuroprotective sAPP(alpha), pharmacological up-regulation of alpha-secretase may provide alternative therapeutic approaches for Alzheimer s disease.
Hooper
N M
NM
Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, UK. n.m.hooper@leeds.ac.uk
Turner
A J
AJ
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D008969:Molecular Sequence Data; D018721:Muscarinic Agonists / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D002800:Cholinesterase Inhibitors; D004967:Estrogens; D018721:Muscarinic Agonists; D013739:Testosterone; 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