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

Abstract

High levels of amyloid- peptide (A) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of A 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 A 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 A due to a change in the approximation of amyloid precursor protein (APP) and the -site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking A function, by using anti-murine A antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates A levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.