Amyloid-ß Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory.

ABSTRACT

High levels of amyloid-ß peptide (Aß) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aß are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aß levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aß due to a change in the approximation of amyloid precursor protein (APP) and the ß-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aß function, by using anti-murine Aß antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aß levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aß, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aß levels and function during LTP. We show that cGMP enhances Aß production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aß, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aß.