title: Cyclic adenosine monophosphate as an endogenous modulator of the amyloid-β precursor protein metabolism.
abstract: Besides playing a pathogenic role in Alzheimer disease, amyloid-beta peptides are normally produced in low amounts in the brain, and several lines of evidence suggest that they can modulate synaptic plasticity and memory. As cyclic adenosine monophosphate (cAMP) is known to be involved in the same processes and the blockade of its degradation by phosphodiesterase 4 inhibitors has consistently shown beneficial effects on cognition, we investigated the possible correlation between this second messenger and Aβ peptides in neuronal N2a cells overexpressing the amyloid-β precursor protein (APP). We herein report that the elevation of endogenous cAMP by rolipram increased APP protein expression and both its amyloidogenic and nonamyloidogenic processing. The effects of rolipram were reproduced by both the cAMP membrane-permeant analog 8Br-cAMP and the forskolin-induced activation of adenylyl cyclase but were not affected by the PKA inhibitor H-89. Our results demonstrate that, in neuronal cells, APP metabolism is physiologically modulated by cAMP and suggest that this might represent an additional mechanism through which the second messenger could influence memory functions.
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Canepa
authors.forename: Cinzia
authors.initials: C
authors.lastname: Domenicotti
authors.forename: Barbara
authors.initials: B
authors.lastname: Marengo
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Marinari
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pronzato
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fedele
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricciarelli
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D020536:Enzyme Activators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D020889:Rolipram / Q000494:pharmacology; D015290:Second Messenger Systems
chemical_list: D016564:Amyloid beta-Protein Precursor; D020536:Enzyme Activators; D058988:Phosphodiesterase 4 Inhibitors; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020889:Rolipram