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Effect of α-Synuclein on Amyloid β-Induced Toxicity: Relevance to Lewy Body Variant of Alzheimer Disease

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Abstract

Alzheimer’s disease, the most prevalent age-related neurodegenerative disease, is characterized by the presence of extracellular senile plaques composed of amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles. More than 50 % of Alzheimer’s disease (AD) patients also exhibit abundant accumulation of α-synuclein (α-Syn)-positive Lewy bodies. This Lewy body variant of AD (LBV-AD) is associated with accelerated cognitive dysfunction and progresses more rapidly than pure AD. In addition, it has been suggested that Aβ and α-Syn can directly interact. In this study we investigated the effect of α-Syn on Aβ-induced toxicity in cortical neurons. In order to mimic the intracellular accumulation of α-Syn observed in the brain of LBV-AD patients, we used valproic acid (VPA) to increase its endogenous expression levels. The release of α-Syn from damaged presynaptic terminals that occurs during the course of the disease was simulated by challenging cells with recombinant α-Syn. Our results showed that either VPA-induced α-Syn upregulation or addition of recombinant α-Syn protect primary cortical neurons from soluble Aβ1-42 decreasing the caspase-3-mediated cell death. It was also found that neuroprotection against Aβ-induced toxicity mediated by α-Syn overexpression involves the PI3K/Akt cell survival pathway. Furthermore, recombinant α-Syn was shown to directly interact with Aβ1-42 and to decrease the levels of Aβ1-42 oligomers, which might explain its neuroprotective effect. In conclusion, we demonstrate that either endogenous or exogenous α-Syn can be neuroprotective against Aβ-induced cell death, suggesting a cell defence mechanism during the initial stages of the mixed pathology.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-beta

LBs:

Lewy bodies

LBV-AD:

Lewy body variant of AD

BSA:

Bovine serum albumin

MTT:

[3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]

DTT:

1,4-Dithiotreitol

ECF:

Enhanced chemifluorescence

DEVD-pNA:

N-Acetyl-Asp-Glu-Val-Asp-p-nitroanilide

GSK-3β:

Glycogen synthase kinase-3β

PMSF:

Phenylmethylsulfonyl fluoride

PVDF:

Polyvinylidene difluoride

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel

α-Syn:

α-Synuclein

TBS:

Tris-buffered saline

TBS-T:

Tris-buffered saline with tween

RT:

Room temperature

VPA:

Valproic acid

References

  1. Alves Da Costa C, Paitel E, Vincent B, Checler F (2002) Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson’s disease. J Biol Chem 277:50980–50984

    Article  PubMed  CAS  Google Scholar 

  2. Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281–7289

    Article  PubMed  CAS  Google Scholar 

  3. Costa RO, Lacor PN, Ferreira IL, Resende R, Auberson YP, Klein WL, Oliveira CR, Rego AC, Pereira CM (2012) Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers. Aging Cell 11:823–833

    Article  PubMed  CAS  Google Scholar 

  4. el-Agnaf OM, Irvine GB (2002) Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem Soc Trans 30:559–565

    Article  PubMed  CAS  Google Scholar 

  5. Emmer KL, Covy JP, Giasson BI (2012) Studies of protein aggregation in A53T -synuclein transgenic, Tg2576 transgenic, and P246L presenilin-1 knock-in cross bred mice. Neurosci Lett 507:137–142

    Article  PubMed  CAS  Google Scholar 

  6. Ferreira IL, Bajouco LM, Mota SI, Auberson YP, Oliveira CR, Rego AC (2012) Amyloid beta peptide 1–42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-d-aspartate receptors in cortical cultures. Cell Calcium 51:95–106

    Article  PubMed  CAS  Google Scholar 

  7. Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF (2010) Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets 11:1193–1206

    Article  PubMed  CAS  Google Scholar 

  8. Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira C (2006) An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis 23:669–678

    Article  PubMed  CAS  Google Scholar 

  9. Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384

    Article  PubMed  CAS  Google Scholar 

  10. Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M et al (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40:1–8

    Article  PubMed  CAS  Google Scholar 

  11. Hashimoto M, Hsu LJ, Rockenstein E, Takenouchi T, Mallory M, Masliah E (2002) alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J Biol Chem 277:11465–11472

    Article  PubMed  CAS  Google Scholar 

  12. Hertz E, Yua CH, Hertz L, Juurlink BHJ, Schousboe A (1989) Preparation of primary cultures of mouse cortical neurons. In: Shahar A, De Vellis J, Vernadakis A, Haber B (eds) A dissection and tissue culture manual of the nervous system. Alan R Liss, New York

    Google Scholar 

  13. Kaneko H, Kakita A, Kasuga K, Nozaki H, Ishikawa A, Miyashita A, Kuwano R, Ito G, Iwatsubo T, Takahashi H, Nishizawa M, Onodera O, Sisodia SS, Ikeuchi T (2007) Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer’s disease. J Neurosci 27:13092–13097

    Article  PubMed  CAS  Google Scholar 

  14. Kaul S, Anantharam V, Kanthasamy A, Kanthasamy AG (2005) Wild-type alpha-synuclein interacts with pro-apoptotic proteins PKCdelta and BAD to protect dopaminergic neuronal cells against MPP+ -induced apoptotic cell death. Brain Res Mol Brain Res 139:137–152

    Article  PubMed  CAS  Google Scholar 

  15. Kazmierczak A, Strosznajder JB, Adamczyk A (2008) alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells. Neurochem Int 53:263–269

    Article  PubMed  CAS  Google Scholar 

  16. Klucken J, Ingelsson M, Shin Y, Irizarry MC, Hedley-Whyte ET, Frosch M, Growdon J, McLean P, Hyman BT (2006) Clinical and biochemical correlates of insoluble alpha-synuclein in dementia with Lewy bodies. Acta Neuropathol 111:101–108

    Article  PubMed  CAS  Google Scholar 

  17. Kraybill ML, Larson EB, Tsuang DW, Teri L, McCormick WC, Bowen JD, Kukull WA, Leverenz JB, Cherrier MM (2005) Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64:2069–2073

    Article  PubMed  CAS  Google Scholar 

  18. Langlais PJ, Thal L, Hansen L, Galasko D, Alford M, Masliah E (1993) Neurotransmitters in basal ganglia and cortex of Alzheimer’s disease with and without Lewy bodies. Neurology 43:1927–1934

    Article  PubMed  CAS  Google Scholar 

  19. Larson ME, Lesné SE (2012) Soluble Aβ oligomer production and toxicity. J Neurochem 120:125–139

    Article  PubMed  CAS  Google Scholar 

  20. Leng Y, Chuang DeM (2006) Endogenous α-syuclein is induced by Valproic Acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci 26:7502–7512

    Article  PubMed  CAS  Google Scholar 

  21. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  PubMed  Google Scholar 

  22. Magrané J, Rosen KM, Smith RC, Walsh K, Gouras GK, Querfurth HW (2005) Intraneuronal beta-amyloid expression downregulates the Akt survival pathway and blunts the stress response. J Neurosci 25:10960–10969

    Article  PubMed  Google Scholar 

  23. Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R (2006) Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer’s and Parkinson’s in dementia with Lewy body disease. Neurochem Res 31(9):1153–1162

    Article  PubMed  CAS  Google Scholar 

  24. Marsh SE, Blurton-Jones M (2012) Examining the mechanisms that link β-amyloid and α-synuclein pathologies. Alzheimers Res Ther 4:11

    Article  PubMed  CAS  Google Scholar 

  25. 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 98:12245–12250

    Article  PubMed  CAS  Google Scholar 

  26. Moreira P, Pereira C, Santos MS, Oliveira CR (2000) Antiox. Redox. Signal 2:317–325

    CAS  Google Scholar 

  27. Musgrove RE, King AE, Dickson TC (2011) Neuroprotective upregulation of endogenous α-synuclein precedes ubiquitination in cultured dopaminergic neurons. Neurotox Res 19:592–602

    Article  PubMed  CAS  Google Scholar 

  28. Musgrove RE, King AE, Dickson TC (2012) α-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK Signalling Pathway. Neurotox Res. doi:10.1007/s12640-012-9352-5

  29. Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, Thal LJ (1998) Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51:351–357

    Article  PubMed  CAS  Google Scholar 

  30. Origlia N, Arancio O, Domenici L, Yan SS (2009) MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE. Expert Rev Neurother 9:1635–1645

    Article  PubMed  CAS  Google Scholar 

  31. 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 132:1093–1101

    Article  PubMed  Google Scholar 

  32. Quilty MC, King AE, Gai WP, Pountney DL, West AK, Vickers JC, Dickson TC (2006) Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol 199:249–256

    Article  PubMed  CAS  Google Scholar 

  33. Ramin M, Azizi P, Motamedi F, Haghparast A, Khodagholi F (2011) Inhibition of JNK phosphorylation reverses memory deficit induced by β-amyloid (1–42) associated with decrease of apoptotic factors. Behav Brain Res 217:424–431

    Article  PubMed  CAS  Google Scholar 

  34. Resende R, Pereira C, Agostinho P, Vieira AP, Malva JO, Oliveira CR (2007) Susceptibility of hippocampal neurons to Aβ peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res 1143:11–21

    Article  PubMed  CAS  Google Scholar 

  35. Resende R, Ferreiro E, Pereira C, Resende de Oliveira C (2008) Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1–42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death. Neuroscience 155:725–737

    Article  PubMed  CAS  Google Scholar 

  36. Resende R, Ferreiro E, Pereira C, Resende de Oliveira C (2008) ER stress in Aβ-induced GSK-3β activation and tau phosphorylation. J Neurosci Res 86:2091–2099

    Article  PubMed  CAS  Google Scholar 

  37. Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, Park CH, Kim S, Kim EM, Lee SH, Lee S, Suh SW, Suh YH (2002) Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J 16:1826–1828

    PubMed  CAS  Google Scholar 

  38. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152:367–372

    PubMed  CAS  Google Scholar 

  39. Yang F, Uéda K, Chen P, Ashe KH, Cole GM (2000) Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein. Brain Res 853:381–383

    Article  PubMed  CAS  Google Scholar 

  40. Yin G, Li LY, Qu M, Luo HB, Wang JZ, Zhou XW (2011) Upregulation of AKT attenuates amyloid-β-induced cell apoptosis. J Alzheimers Dis 25:337–345

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Instituto de Investigação Interdisciplinar (Project reference: III/54/2005), University of Coimbra, Portugal. R Resende’s fellowship: SFRH/BPD/34712/2007.

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Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal

    Rosa Resende, Sueli C. F. Marques, Elisabete Ferreiro, Isaura Simões, Catarina R. Oliveira & Cláudia M. F. Pereira

  2. Faculty of Medicine, University of Coimbra, 3004-517, Coimbra, Portugal

    Catarina R. Oliveira & Cláudia M. F. Pereira

  3. Biocant, Biotechnology Innovation Center, 3060-197, Cantanhede, Portugal

    Isaura Simões

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  1. Rosa Resende
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  2. Sueli C. F. Marques
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  5. Catarina R. Oliveira
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Correspondence to Rosa Resende.

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Rosa Resende and Sueli C. F. Marques have contributed equally to this work.

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Resende, R., Marques, S.C.F., Ferreiro, E. et al. Effect of α-Synuclein on Amyloid β-Induced Toxicity: Relevance to Lewy Body Variant of Alzheimer Disease. Neurochem Res 38, 797–806 (2013). https://doi.org/10.1007/s11064-013-0982-7

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  • DOI: https://doi.org/10.1007/s11064-013-0982-7

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