A large body of evidence demonstrates that cAMP is necessary for the expression of hippocampal LTP and for memory consolidation. Recent studies have shown that, under physiological conditions, LTP in the hippocampus is sustained by endogenously produced amyloid beta (Aß). Thus, we have hypothesised a functional relationship between cAMP, Aß and LTP as a novel molecular mechanism for memory formation. To investigate this possibility, we have first evaluated whether and through what mechanisms cAMP is able to stimulate Aß production, using neuronal cultured cells and rat hippocampal slices. Successively, we have analysed whether the potentiating effects of the PDE4 inhibitor rolipram on hippocampal LTP could be observed in APP knockout slices or in wild type slices treated with anti-Aß antibodies. Our data shows that cAMP enhances APP and Aß42 concentrations through the activation of PKA, but not EPAC. In addition, we have also found that cAMP requires protein synthesis, but not transcription, in order to increase APP and Aß42 levels. Finally, the potentiation of LTP, induced by blocking the degradation of cAMP with rolipram, is absent in APP knockout slices, where Aß is not formed, and is prevented in wild-type slices when the extracellular peptide is blocked by anti-Aß antibodies. In conclusion, our study reveals for the first time a novel cAMP/PKA/APP/Aß molecular pathway controlling the cellular mechanisms of memory formation and adds further support to a physiological role of Aß.
|Titolo:||CAMP-INDUCED AMYLOID BETA PRODUCTION AND ITS ROLE IN LONG TERM POTENTIATION|
|Data di pubblicazione:||2014|
|Appare nelle tipologie:||4.1 Contributo in Atti di convegno|