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Kallab M, Herrera-Vaquero M, Johannesson M, et al. Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy. Front Neurosci. 2018;12:452doi: 10.3389/fnins.2018.00452.
Kallab, M., Herrera-Vaquero, M., Johannesson, M., Eriksson, F., Sigvardson, J., Poewe, W., Wenning, G. K., Nordström, E., & Stefanova, N. (2018). Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy. Frontiers in neuroscience, 12452. https://doi.org/10.3389/fnins.2018.00452
Kallab, Martin, et al. "Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy." Frontiers in neuroscience vol. 12 (2018): 452. doi: https://doi.org/10.3389/fnins.2018.00452
Kallab M, Herrera-Vaquero M, Johannesson M, Eriksson F, Sigvardson J, Poewe W, Wenning GK, Nordström E, Stefanova N. Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy. Front Neurosci. 2018 Jul 04;12:452. doi: 10.3389/fnins.2018.00452. eCollection 2018. PMID: 30022929; PMCID: PMC6039792.
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Front Neurosci. 2018 Jul 04;12:452. doi: 10.3389/fnins.2018.00452. eCollection 2018.

Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy.

Frontiers in neuroscience

Martin Kallab, Marcos Herrera-Vaquero, Malin Johannesson, Fredrik Eriksson, Jessica Sigvardson, Werner Poewe, Gregor K Wenning, Eva Nordström, Nadia Stefanova

Affiliations

  1. Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
  2. BioArctic AB, Stockholm, Sweden.

PMID: 30022929 PMCID: PMC6039792 DOI: 10.3389/fnins.2018.00452

Abstract

Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated α-synuclein. α-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting α-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting α-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial α-synucleinopathy. We used PLP-α-synuclein mice overexpressing human α-synuclein in oligodendrocytes. The animals received either antibodies that recognize α-synuclein or vehicle. Passive immunization mitigated α-synuclein pathology and resulted in reduction of total α-synuclein in the hippocampus, reduction of intracellular accumulation of aggregated α-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric α-synuclein was associated with reduction of the density of activated iba1-positive microglia profiles. However, a shift toward phagocytic microglia was seen after passive immunization of PLP-α-synuclein mice. Lowering of intracellular α-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-α-synuclein mice. In summary, the study provides evidence for the biological efficacy of immunotherapy in a transgenic mouse model of oligodendroglial synucleinopathy. The different availability of the therapeutic antibodies and the variable load of α-synuclein pathology in selected brain regions resulted in differential effects of the immunotherapy that allowed us to propose a model of the underlying mechanisms of antibody-aided α-synuclein clearance.

Keywords: animal model; autophagy; immunotherapy; α-synuclein; α-synuclein clearance

References

  1. EMBO Rep. 2002 Jun;3(6):583-8 - PubMed
  2. Acta Neuropathol. 2014;127(6):861-79 - PubMed
  3. Clin Auton Res. 2015 Feb;25(1):9-17 - PubMed
  4. Exp Neurol. 2017 Dec;298(Pt B):225-235 - PubMed
  5. Neurobiol Dis. 2014 Sep;69:134-43 - PubMed
  6. Auton Neurosci. 2018 May;211:7-14 - PubMed
  7. Am J Pathol. 2005 Mar;166(3):869-76 - PubMed
  8. Mol Neurobiol. 2013 Apr;47(2):575-86 - PubMed
  9. PLoS One. 2011 Apr 29;6(4):e19338 - PubMed
  10. Glia. 2018 Jan;66(1):191-205 - PubMed
  11. J Neurosci. 2018 Jan 24;38(4):1000-1014 - PubMed
  12. J Mov Disord. 2016 Jan;9(1):14-9 - PubMed
  13. Mol Neurodegener. 2015 Mar 19;10:10 - PubMed
  14. J Cereb Blood Flow Metab. 2012 Oct;32(10):1841-52 - PubMed
  15. J Neurosci. 2006 Oct 11;26(41):10558-63 - PubMed
  16. Am J Pathol. 2011 Aug;179(2):954-63 - PubMed
  17. Ann Neurol. 2011 Aug;70(2):194-206 - PubMed
  18. Exp Neurol. 2017 Dec;298(Pt B):172-179 - PubMed
  19. J Neurosci. 2014 Jul 9;34(28):9441-54 - PubMed
  20. Nat Rev Neurosci. 2017 Sep;18(9):515-529 - PubMed
  21. Neurotox Res. 2012 May;21(4):393-404 - PubMed
  22. J Neurochem. 2016 Jan;136(1):172-85 - PubMed
  23. J Neurol Neurosurg Psychiatry. 2018 Feb;89(2):175-184 - PubMed
  24. Neurobiol Dis. 2017 Aug;104:85-96 - PubMed
  25. Synapse. 2014 Mar;68(3):98-106 - PubMed
  26. Mol Neurodegener. 2017 Jul 4;12(1):52 - PubMed
  27. Mov Disord. 2007 Nov 15;22(15):2196-203 - PubMed
  28. Neuroscience. 2015 Aug 27;302:47-58 - PubMed
  29. Nat Med. 2017 Feb 7;23(2):1-13 - PubMed
  30. Acta Neuropathol. 2012 Jul;124(1):37-50 - PubMed
  31. Acta Neuropathol. 2011 Jun;121(6):675-93 - PubMed
  32. FASEB J. 2005 Apr;19(6):533-42 - PubMed
  33. Acta Neuropathol Commun. 2017 Jan 13;5(1):7 - PubMed
  34. PLoS Genet. 2014 May 08;10(5):e1004302 - PubMed
  35. Acta Neuropathol Commun. 2018 Jan 3;6(1):2 - PubMed
  36. Biomolecules. 2015 Apr 14;5(2):435-71 - PubMed
  37. Brain. 2017 May 1;140(5):1420-1436 - PubMed
  38. Prog Neurobiol. 2017 Aug;155:171-193 - PubMed
  39. Glia. 2013 Mar;61(3):349-60 - PubMed
  40. Cell Tissue Res. 2018 Jul;373(1):161-173 - PubMed
  41. Tissue Barriers. 2016 Jan 28;4(1):e1143544 - PubMed
  42. J Neurosci. 2012 Sep 26;32(39):13454-69 - PubMed
  43. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9593-8 - PubMed
  44. PLoS One. 2010 Jan 20;5(1):e8784 - PubMed

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