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Neurotoxicity Research

, Volume 23, Issue 1, pp 69–78 | Cite as

Reciprocal Induction Between α-Synuclein and β-Amyloid in Adult Rat Neurons

  • Shohreh MajdEmail author
  • Fariba Chegini
  • Tim Chataway
  • Xin-Fu Zhou
  • Weiping Gai
Original Article

Abstract

In spite of definite roles for β-amyloid (Aβ) in familial Alzheimer’s disease (AD), the cause of sporadic AD remains unknown. Amyloid senile plaques and Lewy body pathology frequently coexist in neocortical and hippocampal regions of AD and Parkinson’s diseases. However, the relationship between Aβ and α-synuclein (α-Syn), the principle components in the pathological structures, in neuronal toxicity and the mechanisms of their interaction are not well studied. As Aβ and α-Syn accumulate in aging patients, the biological functions and toxicity of these polypeptides in the aging brain may be different from those in young brain. We examined the neurotoxicity influences of Aβ1-42 or α-Syn on mature neurons and the effects of Aβ1-42 or α-Syn on the production of endogenous α-Syn or Aβ1-40 reciprocally using a model of culture enriched with primary neurons from the hippocampus of adult rats. Treatment of neurons with high concentrations of Aβ1-42 or α-Syn caused significant apoptosis of neurons. Following Aβ1-42 treatment at sub apoptotic concentrations, both intra- and extra-cellular α-Syn levels were significantly increased. Reciprocally, the non-toxic levels of α-Syn treatment also increased intra- and extra-cellular Aβ1-40 levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, suppressed α-Syn-induced Aβ1-40 elevation, as well as Aβ1-42-induced α-Syn elevation. Thus, high concentrations of Aβ1-42 and α-Syn exert toxic effects on mature neurons; however, non-toxic concentration treatment of these polypeptides induced the production of each other reciprocally with possible involvement of PI3K pathway.

Keywords

β-Amyloid α-Synuclein Adult neurons Neuronal death Alzheimer’s disease Parkinson’s disease Phosphatidylinositol 3-kinase (PI3K) 

Notes

Acknowledgments

This study was supported by NHMRC grants to Xin-Fu Zhou (595937) and Weiping Gai (535014).

References

  1. Allen SJ, MacGowan SH, Treanor JJ, Feeney R, Wilcock GK, Dawbarn D (1991) Normal beta-NGF content in Alzheimer’s disease cerebral cortex and hippocampus. Neurosci Lett 131:135–139PubMedCrossRefGoogle Scholar
  2. Araujo DM, Cotman CW (1992) Beta-amyloid stimulates glial cells in vitro to produce growth factors that accumulate in senile plaques in Alzheimer’s disease. Brain Res 569:141–145PubMedCrossRefGoogle Scholar
  3. Bowen RL, Smith MA, Harris PL, Kubat Z, Martins RN, Castellani RJ, Perry G, Atwood CS (2002) Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer’s disease pathology. J Neurosci Res 70:514–518PubMedCrossRefGoogle Scholar
  4. Brewer GJ (1997) Isolation and culture of adult rat hippocampal neurons. J Neurosci Methods 71:143–155PubMedCrossRefGoogle Scholar
  5. Brewer GJ (1998) Age-related toxicity to lactate, glutamate, and beta-amyloid in cultured adult neurons. Neurobiol Aging 19:561–568PubMedCrossRefGoogle Scholar
  6. Brewer GJ, Reichensperger JD, Brinton RD (2006) Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiol Aging 27:306–317PubMedCrossRefGoogle Scholar
  7. Cacabelos R, Fernandez-Novoa L, Lombardi V, Corzo L, Pichel V, Kubota Y (2003) Cerebrovascular risk factors in Alzheimer’s disease: brain hemodynamics and pharmacogenomic implications. Neurol Res 25:567–580PubMedCrossRefGoogle Scholar
  8. Chen L, Jin J, Davis J, Zhou Y, Wang Y, Liu J, Lockhart PJ, Zhang J (2007) Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem Biophys Res Commun 356:548–553PubMedCrossRefGoogle Scholar
  9. Chiang HC, Wang L, Xie Z, Yau A, Zhong Y (2010) PI3 kinase signalling is involved in Abeta-induced memory loss in Drosophila. Proc Natl Acad Sci USA 107:7060–7065PubMedCrossRefGoogle Scholar
  10. Christensen DD (2007) Alzheimer’s disease: progress in the development of anti-amyloid disease-modifying therapies. CNS Spectr 12(113–116):119–123Google Scholar
  11. Connor B, Beilharz EJ, Williams C, Synek B, Gluckman PD, Faull RL, Dragunow M (1997) Insulin-like growth factor-I (IGF-I) immunoreactivity in the Alzheimer’s disease temporal cortex and hippocampus. Brain Res Mol Brain Res 49:283–290PubMedCrossRefGoogle Scholar
  12. Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, Canonico PL, Nicoletti F, Sortino MA (1999) Mitotic signalling by beta-amyloid causes neuronal death. FASEB J 13:2225–2234PubMedGoogle Scholar
  13. Crawford JG (1996) Alzheimer’s disease risk factors as related to cerebral blood flow. Med Hypotheses 46:367–377PubMedCrossRefGoogle Scholar
  14. Davis-Salinas J, Saporito-Irwin SM, Cotman CW, Van Nostrand WE (1995) Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells. J Neurochem 65:931–934PubMedCrossRefGoogle Scholar
  15. Donnelly RJ, Friedhoff AJ, Beer B, Blume AJ, Vitek MP (1990) Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Mol Neurobiol 10:485–495PubMedCrossRefGoogle Scholar
  16. El-Agnaf OM, Irvine GB (2002) Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem Soc Trans 30:559–565PubMedCrossRefGoogle Scholar
  17. El-Agnaf OM, Jakes R, Curran MD, Middleton D, Ingenito R, Bianchi E, Pessi A, Neill D, Wallace A (1998) Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Lett 440:71–75PubMedCrossRefGoogle Scholar
  18. Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic Abeta peptide formation. Cell 97:395–406PubMedCrossRefGoogle Scholar
  19. Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640PubMedCrossRefGoogle Scholar
  20. Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, Mathis CA, Elmaleh DR, Shoup T, Fischman AJ, Hyman BT, Growdon JH, Johnson KA (2008) Imaging amyloid deposition in Lewy body diseases. Neurology 71:903–910PubMedCrossRefGoogle Scholar
  21. Heinitz K, Beck M, Schliebs R, Perez-Polo JR (2006) Toxicity mediated by soluble oligomers of beta-amyloid (1-42) on cholinergic SN56.B5.G4 cells. J Neurochem 98:1930–1945PubMedCrossRefGoogle Scholar
  22. Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM (2008) Protein aggregation in the brain: the molecular basis for Alzheimer’s and Parkinson’s diseases. Mol Med 14:451–464PubMedCrossRefGoogle Scholar
  23. Iwata A, Maruyama M, Kanazawa I, Nukina N (2001) Alpha-synuclein affects the MAPK pathway and accelerates cell death. J Biol Chem 276:45320–45329PubMedCrossRefGoogle Scholar
  24. Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B (2004) Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 279:15240–15247PubMedCrossRefGoogle Scholar
  25. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937PubMedCrossRefGoogle Scholar
  26. Kawamoto EM, Lepsch LB, Boaventura MF (2008) Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-d-aspartate signalling pathway in cultured cerebellar cells. J Neurosci Res 86:845–860PubMedCrossRefGoogle Scholar
  27. Ledesma MD, Da Silva JS, Crassaerts K, Delacourte A, De Strooper B, Dotti CG (2000) Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer’s disease brains. EMBO Rep 1:530–535PubMedGoogle Scholar
  28. Lee RK, Knapp S, Wurtman RJ (1999) Prostaglandin E2 stimulates amyloid precursor protein gene expression: inhibition by immunosuppressants. J Neurosci 19:940–947PubMedGoogle Scholar
  29. Lee VM, Giasson BI, Trojanowski JQ (2004) More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134PubMedCrossRefGoogle Scholar
  30. Lesné S, Ali C, Gabriel C, Croci N, MacKenzie ET, Glabe CG, Plotkine M, Marchand-Verrecchia C, Vivien D, Buisson A (2005) NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J Neurosci 25:9367–9377PubMedCrossRefGoogle Scholar
  31. Luo Y, Sunderland T, Wolozin B (1996) Physiologic levels of beta-amyloid activate phosphatidylinositol 3-kinase with the involvement of tyrosine phosphorylation. J Neurochem 67:978–987PubMedCrossRefGoogle Scholar
  32. Majd S, Rastegar K, Zarifkar A, Takhshid MA (2007) Fibrillar beta-amyloid (Abeta) (1-42) elevates extracellular Abeta in cultured hippocampal neurons of adult rats. Brain Res 1185:321–327PubMedCrossRefGoogle Scholar
  33. Majd S, Smardencas A, Parish CL, Drago J (2011) Development of an in vitro model to evaluate the regenerative capacity of adult brain-derived tyrosine hydroxylase-expressing dopaminergic neurons. Neurochem Res 36:967–977PubMedCrossRefGoogle Scholar
  34. Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095–3099PubMedGoogle Scholar
  35. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250PubMedCrossRefGoogle Scholar
  36. Nagy Z (2005) The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer’s disease. J Cell Mol Med 9:531–541PubMedCrossRefGoogle Scholar
  37. Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z, Song M, Xiong J, Bai Y, Pei G (2006) Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nat Med 12:1390–1396PubMedCrossRefGoogle Scholar
  38. Okada T, Wakabayashi M, Ikeda K, Matsuzaki K (2007) Formation of toxic fibrils of Alzheimer’s amyloid beta-protein-(1–40) by monosialoganglioside GM1, a neuronal membrane component. J Mol Biol 371:481–489PubMedCrossRefGoogle Scholar
  39. Oláh J, Vincze O, Virók D, Simon D, Bozsó Z, Tõkési N, Horváth I, Hlavanda E, Kovács J, Magyar A, Szũcs M, Orosz F, Penke B, Ovádi J (2011) Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. J Biol Chem 286:34088–34100PubMedCrossRefGoogle Scholar
  40. Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS 3:1–9Google Scholar
  41. Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, Hassan AH, Jensen PH, El-Agnaf OM (2009) Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 132:1093–1101PubMedCrossRefGoogle Scholar
  42. Patel JR, Brewer GJ (2003) Age-related changes in neuronal glucose uptake in response to glutamate and beta-amyloid. J Neurosci Res 72:527–536PubMedCrossRefGoogle Scholar
  43. Quon D, Catalano R, Cordell B (1990) Fibroblast growth factor induces beta-amyloid precursor mRNA in glial but not neuronal cultured cells. Biochem Biophys Res Commun 167:96–102PubMedCrossRefGoogle Scholar
  44. Raghavan R, Kruijff L, Sterrenburg MD, Rogers BB, Hladik CL, White CL III (2004) Alpha-synuclein expression in the developing human brain. Pediatr Dev Pathol 7:506–516PubMedCrossRefGoogle Scholar
  45. Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA (2000) Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res 61:128–133PubMedCrossRefGoogle Scholar
  46. Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8:447–453PubMedCrossRefGoogle Scholar
  47. Tamo W, Imaizumi T, Tanji K, Yoshida H, Mori F, Yoshimoto M, Takahashi H, Fukuda I, Wakabayashi K, Satoh K (2002) Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer’s disease amyloid, in human cerebral blood vessels. Neurosci Lett 326:5–8PubMedCrossRefGoogle Scholar
  48. Troy CM, Rabacchi SA, Friedman WJ, Frappier TF, Brown K, Shelanski ML (2000) Caspase-2 mediates neuronal cell death induced by beta-amyloid. J Neurosci 20:1386–1392PubMedGoogle Scholar
  49. Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286PubMedCrossRefGoogle Scholar
  50. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876–12882PubMedCrossRefGoogle Scholar
  51. Yang Y, Varvel NH, Lamb BT, Herrup K (2006) Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci 26:775–784PubMedCrossRefGoogle Scholar
  52. Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539–555PubMedCrossRefGoogle Scholar
  53. Ziolkowska B, Gieryk A, Bilecki W, Wawrzczak-Bargiela A, Wedzony K, Chocyk A, Danielson PE, Thomas EA, Hilbush BS, Sutcliffe JG, Przewlocki R (2005) Regulation of alpha-synuclein expression in limbic and motor brain regions of morphine-treated mice. J Neurosci 25:4996–5003PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Shohreh Majd
    • 1
    Email author
  • Fariba Chegini
    • 1
  • Tim Chataway
    • 1
  • Xin-Fu Zhou
    • 1
  • Weiping Gai
    • 1
  1. 1.Department of Human Physiology and Centre for NeuroscienceFlinders UniversityAdelaideAustralia

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