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

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

Mar del Plata

Congreso; LI Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2015

We have previously demonstrated the ability of Aβ peptide to trigger local synaptic signaling. In this work, wecharacterized hippocampal neuronal response to nanomolar concentrations to Aβ oligomers. Even though lipidperoxidation and mitochondrial dysfunction were not detectable in Aβ-treated neurons, the activation ofphosphoinositide-dependent cellular signaling was observed. Akt and ERK1/2 showed to be activated in aphosphatidylinositol 3-kinase (PI3K)-dependent manner. Moreover, Akt was found to translocate from the cytoplasmto the nucleus whereas FoxO3a and phospho-ERK1/2 were found to move in the opposite direction. In the presenceof Aβ, PKC underwent phosphorylation and maturation, both being required for its activation. PKC priming processshowed to be abolished by a PIP2-PLC inhibitor and neomycin (a phosphoinositide chelator). On the other hand, cellviability was found to be finely tuned by phosphoinositide availability in the presence of Aβ, since both chelation ofphosphoinositides and inhibition of PIP2 hydrolysis diminished mitochondrial function. In summary, our resultsshow a key role for a two-branched pro-life PIP2-dependent signaling pathway with consequences in mitochondrialfunction and cell survival: i) the conversion of PIP2 to PIP3 with FoxO3a inactivation, ii) the hydrolysis of PIP2which triggers a multi-step signaling involving ERK1/2 activation.