Background - 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. We also evaluated whether PDE5-Is might modify Amyloid Precursor Protein (APP) expression and the interaction between APP and the β-site APP cleaving enzyme-1 (BACE-1), evaluated by the OptiCAB assay. Finally, 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 when blocking Aβ function. 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 did not modify APP full-length expression but increases the approximation of APP and BACE1. Finally, we demonstrated that the cGMP-induced LTP and memory depended upon Aβ production. In fact, the physiological potentiation of LTP and recognition memory induced by vardenafil was not present if blocking Aβ function - by anti-murine Aβ antibodies or APP knock-out mice. 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.

Amyloid-beta peptide is required for the cGMP-induced long-term potentiation and memory

Puzzo D;Gulisano W;Palmeri A
2016

Abstract

Background - 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. We also evaluated whether PDE5-Is might modify Amyloid Precursor Protein (APP) expression and the interaction between APP and the β-site APP cleaving enzyme-1 (BACE-1), evaluated by the OptiCAB assay. Finally, 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 when blocking Aβ function. 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 did not modify APP full-length expression but increases the approximation of APP and BACE1. Finally, we demonstrated that the cGMP-induced LTP and memory depended upon Aβ production. In fact, the physiological potentiation of LTP and recognition memory induced by vardenafil was not present if blocking Aβ function - by anti-murine Aβ antibodies or APP knock-out mice. 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.
Amyloid-beta; synaptic plasticity; memory; cGMP
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/317376
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