title: The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation.
abstract: γ-Secretase is a large enzyme complex comprising presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1 that mediates the intramembrane proteolysis of a large number of proteins including amyloid precursor protein and Notch. Recently, a novel γ-secretase activating protein (GSAP) was identified that interacts with γ-secretase and the C-terminal fragment of amyloid precursor protein to selectively increase amyloid-β production. In this study we have further characterized the role of endogenous and exogenous GSAP in the regulation of γ-secretase activity and amyloid-β production in vitro. Knockdown of GSAP expression in N2a cells decreased amyloid-β levels. In contrast, overexpression of GSAP in HEK cells expressing amyloid precursor protein or in N2a cells had no overt effect on amyloid-β generation. Likewise, purified recombinant GSAP had no effect on amyloid-β generation in two distinct in vitro γ-secretase assays. In subsequent cellular studies with imatinib, a kinase inhibitor that reportedly prevents the interaction of GSAP with the C-terminal fragment of amyloid precursor protein, a concentration-dependent decrease in amyloid-β levels was observed. However, no interaction between GSAP and the C-terminal fragment of amyloid precursor protein was evident in co-immunoprecipitation studies. In addition, subchronic administration of imatinib to rats had no effect on brain amyloid-β levels. In summary, these findings suggest the roles of GSAP and imatinib in the regulation of γ-secretase activity and amyloid-β generation are uncertain.
authors.affiliation: Department of Therapeutic Area Neurodegenerative Diseases, Merck Serono S.A., Chemin des Mines 9, 1202 Geneva, Switzerland. ishruthssn@gmail.com
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: Julien
authors.initials: J
authors.lastname: Fabrègue
authors.forename: Laurence
authors.initials: L
authors.lastname: Anderes
authors.forename: Solenne
authors.initials: S
authors.lastname: Ousson
authors.forename: Frédéric
authors.initials: F
authors.lastname: Borlat
authors.forename: Valérie
authors.initials: V
authors.lastname: Eligert
authors.forename: Sébastien
authors.initials: S
authors.lastname: Berger
authors.forename: Mitko
authors.initials: M
authors.lastname: Dimitrov
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Alattia
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001549:Benzamides; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C552288:gamma-secretase activating protein, mouse; D000068877:Imatinib Mesylate; D053829:Amyloid Precursor Protein Secretases