Hippocampal neuronal response to amyloid β peptide oligomers. Biological and biophysical insights

Abstract

We have previously demonstrated that oligomeric amyloid β peptide (oAβ), known as the most harmful species of Aβ, concomitant with iron overload led to synaptic injury and local activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAβ exposure both in the presence and absence of iron. HT22 neurons exposed to iron overload displayed increased lipid peroxidation, slight loss of mitochondrial function, and activation of ERK and Akt pathways. oAβ neither induced an increase in lipid peroxidation nor altered mitochondrial function. However, oAβ alone triggered the activation of ERK and Akt, and the coincubation with oAβ/iron restored pAkt and pERK to the control levels. In addition, we also studied the effect of iron, oAβ and both conditions together, on the biophysical state of the plasma membrane by measuring the generalized polarization of the fluorescence probe Laurdan and the fluorescence anisotropy of DPH and TMA-DPH. Both studies showed that the presence of iron (even at the highest concentration tested), oAβ, or both conditions together, did not perturb the lipid order of the membrane. We conclude that oAβ activates signaling pathways in the absence of oxidative stress or membrane disturbances in hippocampal neurons.