Picomolar amyloid-beta modulates synaptic plasticity by acting on the NO/cGMP/CREB pathway

Aims: Abnormally high levels of amyloid-β peptide (Aβ) are likely to play a major role in Alzheimer’s disease (AD). However, we have recently demonstrated that picomolar (pM) concentrations of Aβ42, resembling the physiological levels in the brain, have a positive modulatory effect on long-term potentiation (LTP) and memory by acting on α7-nicotinic receptors. We now provide an in depth investigation of the molecular mechanisms underlying the effect of pM concentrations of Aβ42 on synaptic plasticity. Methods: The type of plasticity that is modulated by pM Aβ42 was evaluated through electrophysiological recordings in hippocampal slices of wild type and α7-KO mice. These studies were associated with analyses of the Aβ characteristics through transmission electron microscopy (TEM) and western blot (WB). Expression of pre- and post-synaptic proteins involved in LTP was evaluated by performing WB on the same slices used for electrophysiology. Results: In wild type, but not α7-KO mice, pM Aβ42 was able to decrease paired-pulse facilitation and to convert early-phase-LTP into late-phase-LTP, without affecting basal synaptic transmission. TEM and WB confirmed the presence of both monomers and oligomers in our preparation. This Aβ42 plastic effect was prevented by inhibition of the NO/cGMP pathway through L-NAME or RP-8Br-cGMPS. Moreover, Aβ42-induced potentiation correlates with an increased expression of VGLUT1, PSD-95, nNOS, p-CREB and BDNF. Conclusions: Low doses of Aβ42 modulate synaptic plasticity by influencing both the pre- and post-synaptic machinery. In particular, electrophysiological and biochemical assays suggest that Aβ42 enhances neurotransmitter release and induces late-LTP via the NO/cGMP/CREB pathway.