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

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

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Lugar: Oregon; Año: 2016

0893-7648

We have previously demonstrated that oligomericamyloid β peptide (oAβ) together with iron overload generatessynaptic injury and activation of several signaling cascades.In this work, we characterized hippocampal neuronalresponse to oAβ. HT22 neurons exposed to 500 nM oAβshowed neither increased lipid peroxidation nor altered mitochondrialfunction. In addition, biophysical studies showedthat oAβ did not perturb the lipid order of the membrane.Interestingly, although no neuronal damage could be demonstrated,oAβ was found to trigger bifurcatedphosphoinositide-dependent signaling in the neuron, onone hand, the phosphorylation of insulin receptor, thephosphatidylinositol 3-kinase (PI3K)-dependent activationof Akt, its translocation to the nucleus and the concomitantphosphorylation, inactivation, and nuclear exclusionof the transcription factor Forkhead Box O3a (FoxO3a), andon the other, phosphoinositide-phospholipase C (PI-PLC)-dependentextracellular signal-regulated kinase 1/2 (ERK1/2) activation.Pharmacological manipulation of the signaling cascadeswas used in order to better characterize the role ofoAβ-activated signals, and mitochondrial function was determinedas a measure of neuronal viability. The inhibition ofPI3K, PI-PLC, and general phosphoinositide metabolism impairedneuronal mitochondrial function. Furthermore, increasedoAβ-induced cell death was observed in the presenceof phosphoinositide metabolism inhibition. Our resultsallow us to conclude that oAβ triggers the activation ofphosphoinositide-dependent signaling, which results in thesubsequent activation of neuroprotective mechanisms thatcould be involved in the determination of neuronal fate.