Phosphoinositides: a two-path signaling in neuronal response to oligomeric amyloid beta-peptide

URANGA, R.; ALZA, N.P.; CONDE, M.; ANTOLLINI, S.; SALVADOR, G.

Conferencia; 56th International Conference on the Bioscience of Lipids; 2015

We have previously demonstrated that oligomeric amyloid β peptide (oAβ) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAβ. HT22 neurons exposed to 500 nM oAβ neither showed increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAβ did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAβ was found to trigger a bifurcated phosphoinositide-dependent signaling in the neuron: on one hand, the PI3K-dependent activation of Akt, its translocation to the nucleus and the concomitant phosphorylation, inactivation, and nuclear exclusion of the transcription factor FoxO3a; on the other hand, the PIP2-PLC dependent PKC maturation and ERK1/2 activation. For better characterizing the role of oAβ-activated signals, pharmacological manipulation of the signaling cascades was used, and mitochondrial function was determined as a measure of neuronal viability. Neomycin, a known inositol phospholipid chelator, impaired neuronal mitochondrial function. In addition, a decreased mitochondrial activity was also observed in the presence of PI3K and PIP2-PLC inhibitors, LY294002 and U73122, respectively. Our results allow us to conclude that nanomolar concentration of oAβ triggers the activation of phosphoinositide-dependent signaling, which results in the subsequent activation of neuroprotective mechanisms that could be involved in the determination of neuronal fate