Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid [beta] Peptide

• Published in: Molecular neurobiology 2017-07, Vol.54 (5), p.3236
• Main Authors: Uranga, Romina María, Alza, Natalia Paola, Conde, Melisa Ailén, Antollini, Silvia Susana, Salvador, Gabriela Alejandra
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Cell death; Extracellular signal-regulated kinase; Forkhead protein; FOXO3 protein; Hippocampus; Inactivation; Inhibition; Insulin; Iron; Lipid peroxidation; Metabolism; Mitochondria; Neurons; Neuroprotection; Peptides; Peroxidation; Phosphoinositides; Phospholipase C; Phosphorylation; Signal transduction; Translocation; β-Amyloid
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-016-9885-3

We have previously demonstrated that oligomeric amyloid [beta] peptide (oA[beta]) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oA[beta]. HT22 neurons exposed to 500 nM oA[beta] showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oA[beta] did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oA[beta] was found to trigger bifurcated phosphoinositide-dependent signaling in the neuron, on one hand, the phosphorylation of insulin receptor, the phosphatidylinositol 3-kinase (PI3K)-dependent activation of Akt, its translocation to the nucleus and the concomitant phosphorylation, inactivation, and nuclear exclusion of the transcription factor Forkhead Box O3a (FoxO3a), and on the other, phosphoinositide-phospholipase C (PI-PLC)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Pharmacological manipulation of the signaling cascades was used in order to better characterize the role of oA[beta]-activated signals, and mitochondrial function was determined as a measure of neuronal viability. The inhibition of PI3K, PI-PLC, and general phosphoinositide metabolism impaired neuronal mitochondrial function. Furthermore, increased oA[beta]-induced cell death was observed in the presence of phosphoinositide metabolism inhibition. Our results allow us to conclude that oA[beta] 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.