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. 1998 Nov;4(11):715–723.

Post-transcriptional contribution of a cAMP-dependent pathway to the formation of alpha- and beta/gamma-secretases-derived products of beta APP maturation in human cells expressing wild-type and Swedish mutated beta APP.

P Marambaud 1, N Chevallier 1, K Ancolio 1, F Checler 1
PMCID: PMC2230337  PMID: 9932109

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.

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