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
Article

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.

Keywords

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

Abbreviations

AD

Alzheimer’s disease

ANOVA

Analysis of variance

APP

Amyloid beta precursor protein

Amyloid β peptide

BSA

Bovine serum albumin

DAG

Diacylglycerol

DCDCDHF

2′,7′-Dichlorofluorescein diacetate

DMEM

Dulbecco’s modified Eagle’s medium

DMSO

Dimethyl sulfoxide

DPH

1,6-diphenyl-1,3,5-hexatrien

DTT

Dithiothreitol

EDTA

Ethylenediaminetetraacetic acid

EM

Electron microscopy

ERK1/2

Extracellular signal-regulated kinases 1/2

FBS

Fetal bovine serum

FoxO3a

Forkhead Box O3a

GP

Generalized polarization

hNRP

Human NAP-related protein

HRP

Horseradish peroxidase

IR

Insulin receptor

LDH

Lactate dehydrogenase

LilrB2

Leukocyte immunoglobulin-like receptor B2

MAPK

Mitogen-activated protein kinase

MTT

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

oAβ

Oligomeric amyloid β peptide

PBS

Phosphate-buffered saline

PI

Phosphoinositide

PI3K

Phosphatidylinositol 3-kinase

PIP2

Phosphatidylinositol bis-phosphate

PI-PLC

Phosphoinositide-phospholipase C

PrPC

Cellular prion protein

TBA

Thiobarbituric acid

TBARS

Thiobarbituric acid-reactive substance

TCA

Trichloroacetic acid

TMA-DPH

1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene

Notes

Acknowledgments

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)

References

  1. 1.
    Klein WL (2013) Synaptotoxic amyloid-beta oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J Alzheimers Dis 33(Suppl 1):S49–S65PubMedGoogle Scholar
  2. 2.
    Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884PubMedGoogle Scholar
  3. 3.
    Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937CrossRefPubMedGoogle Scholar
  4. 4.
    Nimmrich V, Grimm C, Draguhn A, Barghorn S, Lehmann A, Schoemaker H, Hillen H, Gross G et al (2008) Amyloid beta oligomers (A beta(1–42) globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. J Neurosci 28:788–797CrossRefPubMedGoogle Scholar
  5. 5.
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ye C, Walsh DM, Selkoe DJ, Hartley DM (2004) Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation. Neurosci Lett 366:320–325CrossRefPubMedGoogle Scholar
  7. 7.
    Xia M, Cheng X, Yi R, Gao D, Xiong J (2014) The binding receptors of Abeta: an alternative therapeutic target for Alzheimer’s disease. Mol Neurobiol 1–17Google Scholar
  8. 8.
    Wang D, Yuen EY, Zhou Y, Yan Z, Xiang YK (2011) Amyloid beta peptide-(1–42) induces internalization and degradation of beta2 adrenergic receptors in prefrontal cortical neurons. J Biol Chem 286:31852–31863CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Jin Y, Tsuchiya A, Kanno T, Nishizaki T (2015) Amyloid-beta peptide increases cell surface localization of alpha7 ACh receptor to protect neurons from amyloid beta-induced damage. Biochem Biophys Res Commun 468:157–160CrossRefPubMedGoogle Scholar
  10. 10.
    Inestrosa NC, Godoy JA, Vargas JY, Arrazola MS, Rios JA, Carvajal FJ, Serrano FG, Farias GG (2013) Nicotine prevents synaptic impairment induced by amyloid-beta oligomers through alpha7-nicotinic acetylcholine receptor activation. Neuromolecular Med 15:549–569CrossRefPubMedGoogle Scholar
  11. 11.
    Sola VF, Kedikian G, Heredia L, Heredia F, Anel AD, Rosa AL, Lorenzo A (2009) Amyloid-beta precursor protein mediates neuronal toxicity of amyloid beta through Go protein activation. Neurobiol Aging 30:1379–1392CrossRefGoogle Scholar
  12. 12.
    Cecon E, Chen M, Marcola M, Fernandes PA, Jockers R, Markus RP (2015) Amyloid beta peptide directly impairs pineal gland melatonin synthesis and melatonin receptor signaling through the ERK pathway. FASEB J 29:2566–2582CrossRefPubMedGoogle Scholar
  13. 13.
    Bignante EA, Heredia F, Morfini G, Lorenzo A (2013) Amyloid beta precursor protein as a molecular target for amyloid beta—induced neuronal degeneration in Alzheimer’s disease. Neurobiol Aging 34:2525–2537CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Valles AS, Borroni MV, Barrantes FJ (2014) Targeting brain alpha7 nicotinic acetylcholine receptors in Alzheimer’s disease: rationale and current status. CNS Drugs 28:975–987CrossRefPubMedGoogle Scholar
  15. 15.
    Uranga RM, Giusto NM, Salvador GA (2010) Effect of transition metals in synaptic damage induced by amyloid beta peptide. Neuroscience 170:381–389CrossRefPubMedGoogle Scholar
  16. 16.
    Uranga RM, Katz S, Salvador GA (2013) Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress. J Biol Chem 288:19773–19784CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    O’Neill C, Kiely AP, Coakley MF, Manning S, Long-Smith CM (2012) Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer’s disease. Biochem Soc Trans 40:721–727CrossRefPubMedGoogle Scholar
  18. 18.
    Parodi J, Sepulveda FJ, Roa J, Opazo C, Inestrosa NC, Aguayo LG (2010) Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem 285:2506–2514CrossRefPubMedGoogle Scholar
  19. 19.
    Sepulveda FJ, Opazo C, Aguayo LG (2009) Alzheimer beta-amyloid blocks epileptiform activity in hippocampal neurons. Mol Cell Neurosci 41:420–428CrossRefPubMedGoogle Scholar
  20. 20.
    Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J et al (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Uranga RM, Mateos MV, Giusto NM, Salvador GA (2007) Activation of phosphoinositide-3 kinase/Akt pathway by FeSO4 in rat cerebral cortex synaptic endings. J Neurosci Res 85:2924–2932CrossRefPubMedGoogle Scholar
  22. 22.
    Uranga RM, Giusto NM, Salvador GA (2009) Iron-induced oxidative injury differentially regulates PI3K/Akt/GSK3beta pathway in synaptic endings from adult and aged rats. Toxicol Sci 111:331–344CrossRefPubMedGoogle Scholar
  23. 23.
    Hanzel CE, Verstraeten SV (2009) Tl(I) and Tl(III) activate both mitochondrial and extrinsic pathways of apoptosis in rat pheochromocytoma (PC12) cells. Toxicol Appl Pharmacol 236:59–70CrossRefPubMedGoogle Scholar
  24. 24.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  25. 25.
    Parasassi T, De SG, d’Ubaldo A, Gratton E (1990) Phase fluctuation in phospholipid membranes revealed by Laurdan fluorescence. Biophys J 57:1179–1186CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Parasassi T, De SG, Ravagnan G, Rusch RM, Gratton E (1991) Quantitation of lipid phases in phospholipid vesicles by the generalized polarization of Laurdan fluorescence. Biophys J 60:179–189CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shinitzky MYY (1982) Lipid fluidity at the submacroscopic level: determination by fluorescence polarization. Chem Phys Lipids 30:261–282CrossRefGoogle Scholar
  28. 28.
    Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Osborn L, Kunkel S, Nabel GJ (1989) Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 86:2336–2340CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kaiser RD, London E (1998) Location of diphenylhexatriene (DPH) and its derivatives within membranes: comparison of different fluorescence quenching analyses of membrane depth. Biochemistry 37:8180–8190CrossRefPubMedGoogle Scholar
  31. 31.
    Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, Masutani H, Yodoi J et al (2005) Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ 12:19–24CrossRefPubMedGoogle Scholar
  32. 32.
    Lambert JC, Amouyel P (2011) Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Curr Opin Genet Dev 21:295–301CrossRefPubMedGoogle Scholar
  33. 33.
    Mondragon-Rodriguez S, Perry G, Zhu X, Boehm J (2012) Amyloid beta and tau proteins as therapeutic targets for Alzheimer’s disease treatment: rethinking the current strategy. Int J Alzheimers Dis 2012:630182PubMedPubMedCentralGoogle Scholar
  34. 34.
    Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 13:1676–1687PubMedGoogle Scholar
  35. 35.
    Miñano-Molina AJ, Espana J, Martin E, Barneda-Zahonero B, Fado R, Sole M, Trullas R, Saura CA et al (2011) Soluble oligomers of amyloid-beta peptide disrupt membrane trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction. J Biol Chem 286:27311–27321CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70:532–540CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639CrossRefPubMedGoogle Scholar
  38. 38.
    Nunomura A, Tamaoki T, Tanaka K, Motohashi N, Nakamura M, Hayashi T, Yamaguchi H, Shimohama S et al (2010) Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease. Neurobiol Dis 37:731–737CrossRefPubMedGoogle Scholar
  39. 39.
    Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G et al (2009) Reexamining Alzheimer’s disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 18:447–452CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Obrenovich ME, Joseph JA, Atwood CS, Perry G, Smith MA (2002) Amyloid-beta: a (life) preserver for the brain. Neurobiol Aging 23:1097–1099CrossRefPubMedGoogle Scholar
  41. 41.
    Gargantini E, Lazzari L, Settanni F, Taliano M, Trovato L, Gesmundo I, Ghigo E, Granata R (2015) Obestatin promotes proliferation and survival of adult hippocampal progenitors and reduces amyloid-beta-induced toxicity. Mol Cell EndocrinolGoogle Scholar
  42. 42.
    Lilja AM, Porras O, Storelli E, Nordberg A, Marutle A (2011) Functional interactions of fibrillar and oligomeric amyloid-beta with alpha7 nicotinic receptors in Alzheimer’s disease. J Alzheimers Dis 23:335–347PubMedGoogle Scholar
  43. 43.
    Tong L, Balazs R, Thornton PL, Cotman CW (2004) Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci 24:6799–6809CrossRefPubMedGoogle Scholar
  44. 44.
    Bahr BA, Hoffman KB, Yang AJ, Hess US, Glabe CG, Lynch G (1998) Amyloid beta protein is internalized selectively by hippocampal field CA1 and causes neurons to accumulate amyloidogenic carboxyterminal fragments of the amyloid precursor protein. J Comp Neurol 397:139–147CrossRefPubMedGoogle Scholar
  45. 45.
    Wang D, Govindaiah G, Liu R, De Arcangelis V, Cox CL, Xiang YK (2010) Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. FASEB J 24:3511–3521CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wang D, Fu Q, Zhou Y, Xu B, Shi Q, Igwe B, Matt L, Hell JW et al (2013) Beta2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. J Biol Chem 288:10298–10307CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341:1399–1404CrossRefPubMedGoogle Scholar
  48. 48.
    Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lauren J (2014) Cellular prion protein as a therapeutic target in Alzheimer’s disease. J Alzheimers Dis 38:227–244PubMedGoogle Scholar
  50. 50.
    Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66:739–754CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 79:887–902CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Fu W, Jhamandas JH (2003) Beta-amyloid peptide activates non-alpha7 nicotinic acetylcholine receptors in rat basal forebrain neurons. J Neurophysiol 90:3130–3136CrossRefPubMedGoogle Scholar
  53. 53.
    Liu Q, Kawai H, Berg DK (2001) Beta-amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci U S A 98:4734–4739CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Liu Q, Huang Y, Xue F, Simard A, DeChon J, Li G, Zhang J, Lucero L et al (2009) A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. J Neurosci 29:918–929CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Pettit DL, Shao Z, Yakel JL (2001) Beta-amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 21:RC120PubMedGoogle Scholar
  56. 56.
    Dineley KT, Bell KA, Bui D, Sweatt JD (2002) Beta-amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 277:25056–25061CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang Q, Guo S, Zhang X, Tang S, Wang L, Han X, Shao W, Cong L et al (2015) Amyloid beta oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes. Gene 561:76–81CrossRefPubMedGoogle Scholar
  58. 58.
    Kurochkin IV, Goto S (1994) Alzheimer’s beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett 345:33–37CrossRefPubMedGoogle Scholar
  59. 59.
    Xie L, Helmerhorst E, Taddei K, Plewright B, Van BW, Martins R (2002) Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 22:RC221PubMedGoogle Scholar
  60. 60.
    Minoshima S, Cross DJ, Foster NL, Henry TR, Kuhl DE (1999) Discordance between traditional pathologic and energy metabolic changes in very early Alzheimer’s disease. Pathophysiological implications. Ann N Y Acad Sci 893:350–352CrossRefPubMedGoogle Scholar
  61. 61.
    Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 22:246–260CrossRefPubMedGoogle Scholar
  62. 62.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868CrossRefPubMedGoogle Scholar
  63. 63.
    Fukunaga K, Ishigami T, Kawano T (2005) Transcriptional regulation of neuronal genes and its effect on neural functions: expression and function of Forkhead transcription factors in neurons. J Pharmacol Sci 98:205–211CrossRefPubMedGoogle Scholar
  64. 64.
    Nakae J, Park BC, Accili D (1999) Insulin stimulates phosphorylation of the Forkhead transcription factor FKHR on serine 253 through a wortmannin-sensitive pathway. J Biol Chem 274:15982–15985CrossRefPubMedGoogle Scholar
  65. 65.
    Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC et al (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10:138–148CrossRefPubMedPubMedCentralGoogle Scholar

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

Personalised recommendations