Molecular Neurobiology

, Volume 54, Issue 5, pp 3236–3252 | Cite as

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

  • Romina María Uranga
  • Natalia Paola Alza
  • Melisa Ailén Conde
  • Silvia Susana Antollini
  • Gabriela Alejandra Salvador


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.


Amyloid β peptide Phosphoinositides PI3K FoxO PI-PLC ERK1/2 



Alzheimer’s disease


Analysis of variance


Amyloid beta precursor protein

Amyloid β peptide


Bovine serum albumin




2′,7′-Dichlorofluorescein diacetate


Dulbecco’s modified Eagle’s medium


Dimethyl sulfoxide






Ethylenediaminetetraacetic acid


Electron microscopy


Extracellular signal-regulated kinases 1/2


Fetal bovine serum


Forkhead Box O3a


Generalized polarization


Human NAP-related protein


Horseradish peroxidase


Insulin receptor


Lactate dehydrogenase


Leukocyte immunoglobulin-like receptor B2


Mitogen-activated protein kinase


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Oligomeric amyloid β peptide


Phosphate-buffered saline




Phosphatidylinositol 3-kinase


Phosphatidylinositol bis-phosphate


Phosphoinositide-phospholipase C


Cellular prion protein


Thiobarbituric acid


Thiobarbituric acid-reactive substance


Trichloroacetic acid





We thank Dr. Charles Glabe (Department of Molecular Biology and Biochemistry, University of California, Irvine, USA) for kindly providing OC and A11 antibodies. This work was supported by Universidad Nacional del Sur (PGI 24/B179), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT; PICT-2010-0936 and PICT-2013-0987), and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET; PIP 11220120100251).

Supplementary material

12035_2016_9885_MOESM1_ESM.tif (1.1 mb)
Supplementary Fig. 1Negative control, no effect on PI3K was exerted by non-oligomerized Aβ (TIF 1120 kb)
12035_2016_9885_Fig9_ESM.gif (256 kb)

High-resolution image (GIF 255 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Romina María Uranga
    • 1
    • 2
    • 3
  • Natalia Paola Alza
    • 1
    • 2
    • 3
  • Melisa Ailén Conde
    • 1
    • 2
    • 3
  • Silvia Susana Antollini
    • 1
    • 2
    • 3
  • Gabriela Alejandra Salvador
    • 1
    • 2
    • 3
  1. 1.Instituto de Investigaciones Bioquímicas de Bahía BlancaBahía BlancaArgentina
  2. 2.Universidad Nacional del SurBahía BlancaArgentina
  3. 3.Consejo Nacional de Investigaciones Científicas y TécnicasBahía BlancaArgentina

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