PIP2 Signaling: a two-branched pro-life response against oligomeric amyloid beta-peptide

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

Congreso; 51 Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2015

We have previously demonstrated the ability of Aβ peptide to trigger local synaptic signaling. In this work, we characterized hippocampal neuronal response to nanomolar concentrations to Aβ oligomers. Even though lipid peroxidation and mitochondrial dysfunction were not detectable in Aβ-treated neurons, the activation of phosphoinositide-dependent cellular signaling was observed. Akt and ERK1/2 showed to be activated in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. Moreover, Akt was found to translocate from the cytoplasm to the nucleus whereas FoxO3a and phospho-ERK1/2 were found to move in the opposite direction. In the presence of Aβ, PKC underwent phosphorylation and maturation, both being required for its activation. PKC priming process showed to be abolished by a PIP2-PLC inhibitor and neomycin (a phosphoinositide chelator). On the other hand, cell viability was found to be finely tuned by phosphoinositide availability in the presence of Aβ, since both chelation of phosphoinositides and inhibition of PIP2 hydrolysis diminished mitochondrial function. In summary, our results show a key role for a two-branched pro-life PIP2-dependent signaling pathway with consequences in mitochondrial function and cell survival: i) the conversion of PIP2 to PIP3 with FoxO3a inactivation, ii) the hydrolysis of PIP2 which triggers a multi-step signaling involving ERK1/2 activation.