Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid Beta Peptide

URANGA, ROMINA MARÍA; ALZA, NATALIA PAOLA; CONDE, MELISA AILÉN; ANTOLLINI, SILVIA SUSANA; SALVADOR, GABRIELA ALEJANDRA

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Lugar: Oregon; Año: 2016

0893-7648

We have previously demonstrated that oligomeric amyloid beta peptide (oAB) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAB.HT22 neurons exposed to 500 nM oAB showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAB did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAB was found to trigger bifurcated phosphoinositidedependent signaling in the neuron: on one hand, the phosphorylation of insulinreceptor, 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 FoxO3a; and on the other, phosphoinositide phospholipase C (PI-PLC) dependent extracellular signal-regulated kinases 1/2 (ERK1/2) activation. Pharmacological manipulation of the signaling cascades was used in order to better characterize the role of oAB-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 oAβ-induced cell death was observed in the presence of phosphoinositide metabolism inhibition. Our results allow us to conclude that nanomolar concentrations of oAB trigger 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.