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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes

Authors: Gabriel Gustafsson, Veronica Lindström, Jinar Rostami, Eva Nordström, Lars Lannfelt, Joakim Bergström, Martin Ingelsson, Anna Erlandsson

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson’s disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria.

Methods

The aim of the present study was to investigate if the accumulation of α-syn in astrocytes can be affected by α-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to α-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies.

Results

In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added α-syn, and consequently, the α-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer-induced mitochondrial impairment.

Conclusions

Our results demonstrate that oligomer-selective antibodies can prevent α-syn accumulation and mitochondrial dysfunction in cultured astrocytes.
Literature
1.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998;95:6469–73.CrossRefPubMedPubMedCentral
2.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.CrossRefPubMed
3.
El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 2006;20:419–25.CrossRefPubMed
4.
5.
Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B, Kostka M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27:9220–32.CrossRefPubMed
6.
Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A. 2011;108:4194–9.CrossRefPubMedPubMedCentral
7.
Chinta SJ, Mallajosyula JK, Rane A, Andersen JK. Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett. 2010;486:235–9.CrossRefPubMedPubMedCentral
8.
Luth ES, Stavrovskaya IG, Bartels T, Kristal BS, Selkoe DJ. Soluble, prefibrillar alpha-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J Biol Chem. 2014;289:21490–507.CrossRefPubMedPubMedCentral
9.
Lindström V, Fagerqvist T, Nordstrom E, Eriksson F, Lord A, Tucker S, Andersson J, Johannesson M, Schell H, Kahle PJ, et al. Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] alpha-synuclein mice. Neurobiol Dis. 2014;69:134–43.CrossRefPubMed
10.
Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, Desplats P, Masliah E, Lee SJ. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32:13454–69.CrossRefPubMedPubMedCentral
11.
Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, Santic R, Meindl S, Vigl B, Smrzka O, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127:861–79.CrossRefPubMedPubMedCentral
12.
Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46:857–68.CrossRefPubMed
13.
Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6:e19338.CrossRefPubMedPubMedCentral
14.
Braak H, Sastre M, Del Tredici K. Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol. 2007;114:231–41.CrossRefPubMed
15.
Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H. NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol. 2000;99:14–20.CrossRefPubMed
16.
Terada S, Ishizu H, Yokota O, Tsuchiya K, Nakashima H, Ishihara T, Fujita D, Ueda K, Ikeda K, Kuroda S. Glial involvement in diffuse Lewy body disease. Acta Neuropathol. 2003;105:163–9.PubMed
17.
Croisier E, Graeber MB. Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol. 2006;112:517–30.CrossRefPubMed
18.
PH T, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 1998;44:415–22.CrossRef
19.
Iseki E, Marui W, Akiyama H, Ueda K, Kosaka K. Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using alpha-synuclein-immunohistochemistry. Neurosci Lett. 2000;286:69–73.CrossRefPubMed
20.
21.
22.
Verkhratsky A, Nedergaard M, Hertz L. Why are astrocytes important? Neurochem Res. 2015;40:389–401.CrossRefPubMed
23.
Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. 2014;565:30–8.CrossRefPubMed
24.
Piovesan E, Castilhos C, Pozza R, Michelon TF, Seelig DC, Santos AF, Bittar E, Keitel E, Goldani JC, Garcia CD, et al. Hemolytic-uremic syndrome after kidney transplantation. Transplant Proc. 2002;34:2779–80.CrossRefPubMed
25.
Lindström V, Gustafsson G, Sanders LH, Howlett EH, Sigvardson J, Kasrayan A, Ingelsson M, Bergström J, Erlandsson A. Extensive uptake of alpha-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci. 2017;
26.
Fagerqvist T, Lindström V, Nordstrom E, Lord A, Tucker SM, Su X, Sahlin C, Kasrayan A, Andersson J, Welander H, et al. Monoclonal antibodies selective for alpha-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and transgenic mice expressing the disease-causing A30P mutation. J Neurochem. 2013;
27.
Söllvander S, Nikitidou E, Brolin R, Soderberg L, Sehlin D, Lannfelt L, Erlandsson A. Accumulation of amyloid-beta by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016;11:38.CrossRefPubMedPubMedCentral
28.
Davis AA, Temple S. A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature. 1994;372:263–6.CrossRefPubMed
29.
Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM, McKay RD. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 1996;10:3129–40.CrossRefPubMed
30.
Ravin R, Hoeppner DJ, Munno DM, Carmel L, Sullivan J, Levitt DL, Miller JL, Athaide C, Panchision DM, McKay RD. Potency and fate specification in CNS stem cell populations in vitro. Cell Stem Cell. 2008;3:670–80.CrossRefPubMed
31.
Nasstrom T, Fagerqvist T, Barbu M, Karlsson M, Nikolajeff F, Kasrayan A, Ekberg M, Lannfelt L, Ingelsson M, Bergstrom J. The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties. Free Radic Biol Med. 2011;50:428–37.CrossRefPubMed
32.
Näsström T, Goncalves S, Sahlin C, Nordstrom E, Screpanti Sundquist V, Lannfelt L, Bergstrom J, Outeiro TF, Ingelsson M. Antibodies against alpha-synuclein reduce oligomerization in living cells. PLoS One. 2011;6:e27230.CrossRefPubMedPubMedCentral
33.
Magnusson K, Sehlin D, Syvanen S, Svedberg MM, Philipson O, Soderberg L, Tegerstedt K, Holmquist M, Gellerfors P, Tolmachev V, et al. Specific uptake of an amyloid-beta protofibril-binding antibody-tracer in AbetaPP transgenic mouse brain. J Alzheimers Dis. 2013;37:29–40.PubMed
34.
Lux A, Yu X, Scanlan CN, Nimmerjahn F. Impact of immune complex size and glycosylation on IgG binding to human FcgammaRs. J Immunol. 2013;190:4315–23.CrossRefPubMed
35.
Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23:41–51.CrossRefPubMed
36.
Kasturirangan S, Rainey GJ, Xu L, Wang X, Portnoff A, Chen T, Fazenbaker C, Zhong H, Bee J, Zeng Z, et al. Targeted Fcgamma receptor (FcgammaR)-mediated clearance by a biparatopic bispecific antibody. J Biol Chem. 2017;292:4361–70.CrossRefPubMedPubMedCentral
37.
Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, Patrick C, Ubhi K, Nuber S, Sacayon P, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci. 2014;34:9441–54.CrossRefPubMedPubMedCentral
38.
Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, Luk KC, Lee VM. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep. 2014;7:2054–65.CrossRefPubMedPubMedCentral
39.
Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Muller V, Odoy S, Fujiwara H, Hasegawa M, et al. Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest. 2002;110:1429–39.CrossRefPubMedPubMedCentral
40.
Loov C, Hillered L, Ebendal T, Erlandsson A. Engulfing astrocytes protect neurons from contact-induced apoptosis following injury. PLoS One. 2012;7:e33090.CrossRefPubMedPubMedCentral
41.
Jones RS, Minogue AM, Connor TJ, Lynch MA. Amyloid-beta-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J NeuroImmune Pharmacol. 2013;8:301–11.CrossRefPubMed
42.
Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC, Thompson A, Chen C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504:394–400.CrossRefPubMedPubMedCentral
43.
Chang GH, Barbaro NM, Pieper RO. Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells. Neuro-Oncology. 2000;2:174–83.CrossRefPubMedPubMedCentral
44.
Magnus T, Chan A, Linker RA, Toyka KV, Gold R. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system. J Neuropathol Exp Neurol. 2002;61:760–6.CrossRefPubMed
45.
Sokolowski JD, Nobles SL, Heffron DS, Park D, Ravichandran KS, Mandell JW. Brain-specific angiogenesis inhibitor-1 expression in astrocytes and neurons: implications for its dual function as an apoptotic engulfment receptor. Brain Behav Immun. 2011;25:915–21.CrossRefPubMed
46.
Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia. 2013;61:349–60.CrossRefPubMedPubMedCentral
47.
Victoria GS, Arkhipenko A, Zhu S, Syan S, Zurzolo C. Astrocyte-to-neuron intercellular prion transfer is mediated by cell-cell contact. Sci Rep. 2016;6:20762.CrossRefPubMedPubMedCentral
48.
Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, Kosberg K, Shen J, Rockenstein E, Patrick C, Adame A, et al. ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther. 2014;22:1753–67.CrossRefPubMedPubMedCentral
49.
Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40:200–10.CrossRefPubMed
50.
51.
Guardia-Laguarta C, Area-Gomez E, Rub C, Liu Y, Magrane J, Becker D, Voos W, Schon EA, Przedborski S. Alpha-synuclein is localized to mitochondria-associated ER membranes. J Neurosci. 2014;34:249–59.CrossRefPubMedPubMedCentral
52.
53.
Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A. Glia: the fulcrum of brain diseases. Cell Death Differ. 2007;14:1324–35.CrossRefPubMed
54.
Faroni A, Rothwell SW, Grolla AA, Terenghi G, Magnaghi V, Verkhratsky A. Differentiation of adipose-derived stem cells into Schwann cell phenotype induces expression of P2X receptors that control cell death. Cell Death Dis. 2013;4:e743.CrossRefPubMedPubMedCentral
55.
Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodriguez JJ, Nedergaard M. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro. 2012;4.
Metadata
Title
Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes
Authors
Gabriel Gustafsson
Veronica Lindström
Jinar Rostami
Eva Nordström
Lars Lannfelt
Joakim Bergström
Martin Ingelsson
Anna Erlandsson
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1018-z

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