Stimulation of the amyloid‐β precursor protein metabolism by cAMP

Abstract

Besides playing a pathogenic role in Alzheimer disease, amyloid‐β (Aβ) 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 non‐amyloidogenic processing. The effects of rolipram were reproduced by both the cAMP membrane‐permeant analogue 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. This work was supported by grants from the Alzheimer's Association and the Italian Ministry of University and Research (PRIN 2009M8FKBB_002).