Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy

Molecular Neurodegeneration

Volumn 10, Issue 1, 2015, Pages

  Mandler, Markus ^a   Valera, Elvira ^b   Rockenstein, Edward ^b   Mante, Michael ^b   Weninger, Harald ^a   Patrick, Christina ^b   Adame, Anthony ^b   Schmidhuber, Sabine ^a   Santic, Radmila ^a   Schneeberger, Achim ^a   Schmidt, Walter ^a   Mattner, Frank ^a   Masliah, Eliezer ^b,c  

^a AFFiRiS GmbH   (Austria)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Active immunization; AFFITOPE ; Alpha synuclein; Immunotherapy; Multiple system atrophy

Indexed keywords

AFFITOPE; ALPHA SYNUCLEIN; CASPASE 3; PEPTIDE VACCINE; UNCLASSIFIED DRUG;

ACTIVE IMMUNIZATION; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBODY PRODUCTION; ANTIBODY TITER; ANTIGEN ANTIBODY COMPLEX; ARTICLE; ASTROCYTE; CONTROLLED STUDY; CORPUS CALLOSUM; CORPUS STRIATUM; DEMYELINATION; DRUG EFFICACY; GLIA CELL; IMMUNE RESPONSE; IMMUNOGENICITY; IMMUNOREACTIVITY; MICROGLIA; MOUSE; NEOCORTEX; NERVE DEGENERATION; NONHUMAN; OLIGODENDROGLIA; PROTEIN AGGREGATION; SHY DRAGER SYNDROME; VACCINATION; ANIMAL; CYTOLOGY; DEMYELINATING DISEASES; DISEASE MODEL; IMMUNOLOGY; METABOLISM; MULTIPLE SYSTEM ATROPHY; NERVE CELL; PARKINSONISM; PATHOLOGY; PROCEDURES; TRANSGENIC MOUSE;

MUS MUSCULUS;

ALPHA-SYNUCLEIN; ANIMALS; ASTROCYTES; DEMYELINATING DISEASES; DISEASE MODELS, ANIMAL; MICE, TRANSGENIC; MICROGLIA; MULTIPLE SYSTEM ATROPHY; NEURONS; OLIGODENDROGLIA; PARKINSONIAN DISORDERS; VACCINATION;

EID: 84928533692     PISSN: None     EISSN: 17501326     Source Type: Journal    
DOI: 10.1186/s13024-015-0008-9     Document Type: Article

References (56)

1. Dickson DW, Lin W, Liu WK, Yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol. 1999;9:721-32.
2. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain J Neurology. 1994;117(Pt 4):835-45.
3. Lantos PL, Papp MI. Cellular pathology of multiple system atrophy: a review. J Neurol Neurosurg Psychiatry. 1994;57:129-33.
4. Jellinger KA. Neuropathology and pathophysiology of multiple system atrophy. Neuropathol Appl Neurobiol. 2012;38:379-80. author reply 381.
5. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. 1989;94:79-100.
6. Lee SJ. Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease. J Molecular Neuroscie MN. 2008;34:17-22.
7. Angot E, Brundin P. Dissecting the potential molecular mechanisms underlying alpha-synuclein cell-to-cell transfer in Parkinson's disease. Parkinsonism Relat Disord. 2009;15 Suppl 3:S143-7.
8. Lee SJ, Desplats P, Sigurdson C, Tsigelny I, Masliah E. Cell-to-cell transmission of non-prion protein aggregates. Nat Rev Neurol. 2010;6:702-6.
9. Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A. 2013;110:19555-60.
10. Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T, et al. Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia. 2014;62:964-70.
11. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010;285:9262-72.
12. Lee HJ, Kim C, Lee SJ. Alpha-synuclein stimulation of astrocytes: Potential role for neuroinflammation and neuroprotection. Oxid Med Cell Longev. 2010;3:283-7.
13. Fellner L, Stefanova N. The Role of Glia in Alpha-Synucleinopathies. Mol Neurobiol. 2012;47:575-86.
14. Lee HJ, Baek SM, Ho DH, Suk JE, Cho ED, Lee SJ. Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers. Exp Mol Med. 2011;43:216-22.
15. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012;7:42.
16. Lee SJ, Desplats P, Lee HJ, Spencer B, Masliah E. Cell-to-cell transmission of α-synuclein aggregates. Methods Mol Biol. 2012;849:347-59.
17. Angot E, Steiner JA, Lema Tome CM, Ekstrom P, Mattsson B, Bjorklund A, et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One. 2012;7:e39465.
18. Valera E, Masliah E. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol Ther. 2013;138:311-22.
19. Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014;127:861-79.
20. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005;46:857-68.
21. Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6:e19338.
22. Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, Luk KC, et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Reports. 2014;7:2054-65.
23. Schneeberger A, Mandler M, Mattner F, Schmidt W. Vaccination for Parkinson's disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S11-3.
24. Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin. 2010;6:948-52.
25. Qin Z, Hu D, Han S, Reaney SH, Di Monte DA, Fink AL. Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. J Biol Chem. 2007;282:5862-70.
26. Mandler M, Rockenstein E, Ubhi K, Hansen L, Adame A, Michael S, et al. Detection of peri-synaptic amyloid-β pyroglutamate aggregates in early stages of Alzheimer's disease and in AβPP transgenic mice using a novel monoclonal antibody. J Alzheimers Dis. 2012;28:783-94.
27. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, et al. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32:13454-69.
28. Valera E, Ubhi K, Mante M, Rockenstein E, Masliah E. Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia. 2014;62:317-37.
29. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720-32.
30. Kamegai M, Niijima K, Kunishita T, Nishizawa M, Ogawa M, Araki M, et al. Interleukin 3 as a trophic factor for central cholinergic neurons in vitro and in vivo. Neuron. 1990;4:429-36.
31. Muhl H, Pfeilschifter J. Anti-inflammatory properties of pro-inflammatory interferon-gamma. Int Immunopharmacol. 2003;3:1247-55.
32. Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, et al. Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci. 2005;25:10689-99.
33. Ubhi K, Inglis C, Mante M, Patrick C, Adame A, Spencer B, et al. Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of alpha-synucleinopathy. Exp Neurol. 2012;234:405-16.
34. Halliday G. Clinicopathological aspects of motor parkinsonism. Parkinsonism Relat Disord. 2007;13 Suppl 3:S208-10.
35. Lee HJ, Suk JE, Bae EJ, Lee SJ. Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008;372:423-8.
36. Bach P, Tschäpe JA, Kopietz F, Braun G, Baade JK, Wiederhold KH, et al. Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice. J Immunol. 2009;182:7613-24.
37. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000;408:982-5.
38. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173-7.
39. Solomon B. Active immunization against Alzheimer's beta-amyloid peptide using phage display technology. Vaccine. 2007;25:3053-6.
40. Troquier L, Caillierez R, Burnouf S, Fernandez-Gomez FJ, Grosjean ME, Zommer N, et al. Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res. 2012;9:397-405.
41. Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007;27:9115-29.
42. Sigurdsson EM, Brown DR, Daniels M, Kascsak RJ, Kascsak R, Carp R, et al. Immunization delays the onset of prion disease in mice. Am J Pathol. 2002;161:13-7.
43. Miller TW, Shirley TL, Wolfgang WJ, Kang X, Messer A. DNA vaccination against mutant huntingtin ameliorates the HDR6/2 diabetic phenotype. Mol Ther. 2003;7:572-9.
44. Luthi-Carter R. Progress towards a vaccine for Huntington's disease. Mol Ther. 2003;7:569-70.
45. Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, 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.
46. Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, Kosberg K, et al. ESCRT-mediated Uptake and Degradation of Brain-targeted alpha-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo. Molecular Therapy J Am Soc Gene Therapy. 2014;22:1753-67.
47. Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J. Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol. 1998;153:735-44.
48. Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A. 2013;110:19555-60.
49. Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014;62:387-98.
50. Rockenstein E, Ubhi K, Inglis C, Mante M, Patrick C, Adame A, et al. Neuronal to oligodendroglial alpha-synuclein redistribution in a double transgenic model of multiple system atrophy. Neuroreport. 2012;23:259-64.
51. Lee HJ, Choi C, Lee SJ. Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem. 2002;277:671-8.
52. Kohler G, Milstein C. Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion. Eur J Immunol. 1976;6:511-9.
53. Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, et al. Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci. 2010;30:6236-46.
54. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci. 2009;29:13578-88.
55. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One. 2010;5:e9313.
56. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000;287:1265-9.