title: Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid β Peptide.
abstract: We have previously demonstrated that oligomeric amyloid β peptide (oAβ) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAβ. HT22 neurons exposed to 500 nM oAβ showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAβ did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAβ 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 oAβ-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 oAβ 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.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, La Carrindanga Km 7, 8000, Bahía Blanca, Buenos Aires, Argentina.|Universidad Nacional del Sur, Bahía Blanca, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
authors.forename: Romina María
authors.initials: RM
authors.lastname: Uranga
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, La Carrindanga Km 7, 8000, Bahía Blanca, Buenos Aires, Argentina.|Universidad Nacional del Sur, Bahía Blanca, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
authors.forename: Natalia Paola
authors.initials: NP
authors.lastname: Alza
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, La Carrindanga Km 7, 8000, Bahía Blanca, Buenos Aires, Argentina.|Universidad Nacional del Sur, Bahía Blanca, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
authors.forename: Melisa Ailén
authors.initials: MA
authors.lastname: Conde
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, La Carrindanga Km 7, 8000, Bahía Blanca, Buenos Aires, Argentina.|Universidad Nacional del Sur, Bahía Blanca, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
authors.forename: Silvia Susana
authors.initials: SS
authors.lastname: Antollini
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, La Carrindanga Km 7, 8000, Bahía Blanca, Buenos Aires, Argentina. salvador@criba.edu.ar.|Universidad Nacional del Sur, Bahía Blanca, Argentina. salvador@criba.edu.ar.|Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina. salvador@criba.edu.ar.
authors.forename: Gabriela Alejandra
authors.initials: GA
authors.lastname: Salvador
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D066329:Protein Aggregates; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D010716:Phosphatidylinositols; D066329:Protein Aggregates; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Amyloid β peptide; ERK1/2; FoxO; PI-PLC; PI3K; Phosphoinositides