P Marambaud1, N Chevallier, K Ancolio, F Checler. 1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice-Sophia Antipolis, Valbonne, France.
Abstract
BACKGROUND: The physiopathological maturation of the beta-amyloid precursor protein can be modulated by effectors targeting a protein kinase C-dependent pathway. These agents increase the recovery of APP alpha, the physiological alpha-secretase-derived product of beta APP processing, and concomittantly lower the production of the pathogenic beta/gamma-secretase-derived A beta fragment. METHODS: We set up stably transfected HEK293 cells expressing wild-type or Swedish mutated beta APP. By combined metabolic labeling and/or immunoprecipitation procedures, we assessed the effect of various cAMP effectors on the production of the beta APP maturation products A beta 40, A beta 42, APP alpha, and its C-terminal counterpart. RESULTS: We show here that the cAMP-dependent protein kinase (PKA) effectors, dibutyryl-cAMP (dBut-cAMP) and forskolin, but not the inactive analog dideoxyforskolin, enhance the secretion of APP alpha and the intracellular production of its C-terminal counterpart (p10) in stably transfected HEK293 cells. The above agonists also drastically increase both A beta 40 and A beta 42 secretions and intracellular A beta recovery. The same influence was observed with HEK293 cells overexpressing the Swedish mutated beta APP. We attempted to delineate the relative contribution of transcriptional and post-transcriptional events in the cAMP-mediated response. We show here that the dBut-cAMP and forskolin-induced increase of APP alpha and A beta s secretions is not prevented by the transcription inhibitor actinomycin D. CONCLUSION: Our data suggest a major contribution of post-transcriptional events in the cAMP-dependent effect on beta APP maturation. It appears likely that cAMP triggers the PKA-dependent phosphorylation of a protein involved in beta APP maturation and occurring upstream to alpha- and beta/gamma-secretase cleavages.
BACKGROUND: The physiopathological maturation of the beta-amyloid precursor protein can be modulated by effectors targeting a protein kinase C-dependent pathway. These agents increase the recovery of APP alpha, the physiological alpha-secretase-derived product of beta APP processing, and concomittantly lower the production of the pathogenic beta/gamma-secretase-derived A beta fragment. METHODS: We set up stably transfected HEK293 cells expressing wild-type or Swedish mutated beta APP. By combined metabolic labeling and/or immunoprecipitation procedures, we assessed the effect of various cAMP effectors on the production of the beta APP maturation products A beta 40, A beta 42, APP alpha, and its C-terminal counterpart. RESULTS: We show here that the cAMP-dependent protein kinase (PKA) effectors, dibutyryl-cAMP (dBut-cAMP) and forskolin, but not the inactive analog dideoxyforskolin, enhance the secretion of APP alpha and the intracellular production of its C-terminal counterpart (p10) in stably transfected HEK293 cells. The above agonists also drastically increase both A beta 40 and A beta 42 secretions and intracellular A beta recovery. The same influence was observed with HEK293 cells overexpressing the Swedish mutated beta APP. We attempted to delineate the relative contribution of transcriptional and post-transcriptional events in the cAMP-mediated response. We show here that the dBut-cAMP and forskolin-induced increase of APP alpha and A beta s secretions is not prevented by the transcription inhibitor actinomycin D. CONCLUSION: Our data suggest a major contribution of post-transcriptional events in the cAMP-dependent effect on beta APP maturation. It appears likely that cAMP triggers the PKA-dependent phosphorylation of a protein involved in beta APP maturation and occurring upstream to alpha- and beta/gamma-secretase cleavages.
Authors: F S Esch; P S Keim; E C Beattie; R W Blacher; A R Culwell; T Oltersdorf; D McClure; P J Ward Journal: Science Date: 1990-06-01 Impact factor: 47.728
Authors: C L Masters; G Simms; N A Weinman; G Multhaup; B L McDonald; K Beyreuther Journal: Proc Natl Acad Sci U S A Date: 1985-06 Impact factor: 11.205
Authors: M Shoji; T E Golde; J Ghiso; T T Cheung; S Estus; L M Shaffer; X D Cai; D M McKay; R Tintner; B Frangione Journal: Science Date: 1992-10-02 Impact factor: 47.728
Authors: Donald K Blumenthal; Jeffrey Copps; Eric V Smith-Nguyen; Ping Zhang; William T Heller; Susan S Taylor Journal: J Biol Chem Date: 2014-08-11 Impact factor: 5.157
Authors: K Ancolio; C Dumanchin; H Barelli; J M Warter; A Brice; D Campion; T Frébourg; F Checler Journal: Proc Natl Acad Sci U S A Date: 1999-03-30 Impact factor: 11.205
Authors: Wang-Xia Wang; Bernard W Rajeev; Arnold J Stromberg; Na Ren; Guiliang Tang; Qingwei Huang; Isidore Rigoutsos; Peter T Nelson Journal: J Neurosci Date: 2008-01-30 Impact factor: 6.167
Authors: V Chouraki; R F A G De Bruijn; J Chapuis; J C Bis; C Reitz; S Schraen; C A Ibrahim-Verbaas; B Grenier-Boley; C Delay; R Rogers; F Demiautte; A Mounier; A L Fitzpatrick; C Berr; J-F Dartigues; A G Uitterlinden; A Hofman; M Breteler; J T Becker; M Lathrop; N Schupf; A Alpérovitch; R Mayeux; C M van Duijn; L Buée; P Amouyel; O L Lopez; M A Ikram; C Tzourio; J-C Lambert Journal: Mol Psychiatry Date: 2014-02-18 Impact factor: 15.992
Authors: Kévin Baranger; Yannick Marchalant; Amandine E Bonnet; Nadine Crouzin; Alex Carrete; Jean-Michel Paumier; Nathalie A Py; Anne Bernard; Charlotte Bauer; Eliane Charrat; Katrin Moschke; Mothoharu Seiki; Michel Vignes; Stefan F Lichtenthaler; Frédéric Checler; Michel Khrestchatisky; Santiago Rivera Journal: Cell Mol Life Sci Date: 2015-07-23 Impact factor: 9.261