Amyloid-beta peptide is needed for cGMP-induced long-term potentiation and memory [FENS Forum 2016]

Aim: Accumulation of amyloid-beta (Aβ) has been related to Alzheimer’s disease pathogenesis. However, in the healthy brain, low concentrations of Aβ are necessary for physiological long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we have investigated whether cGMP might influence Aβ production and function during LTP and memory in physiological conditions.Methods: We first evaluated whether an increase of cGMP levels by phosphodiesterase-5 inhibitors (PDE5-Is), such as sildenafil and vardenafil, might affect Aβ levels in Neuro-2a (N2a) cells and hippocampal slices. Then, we performed electrophysiological experiments on hippocampal slices and behavioral studies (novel object recognition) to analyze whether the vardenafil-induced enhancement of LTP and memory was still present in mice lacking Amyloid Precursor Protein (APP KO). Results: We showed that the increase of intracellular cGMP after a treatment with sildenafil or vardenafil induced a parallel increase of Aβ levels in N2A cells and hippocampal slices. This effect was reduced by the guanylyl cyclase inhibitor ODQ. Vardenafil was not able to induce the physiological potentiation of LTP and recognition memory in APP KO mice compared to wild type. Conclusions: The increase of cGMP positively modulates Aβ production, which, in turn boosts synaptic plasticity and memory. The lack of effect of PDE5-Is in APP KO mice suggests that Aβ is needed for the cGMP-induced enhancement of LTP and memory. Thus, PDE5-Is might work as cognitive enhancers via a positive modulation of Aβ at physiological concentrations in the brain.