Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

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

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

Published in: Molecular Neurodegeneration | Issue 1/2015

Login to get access

Abstract

Background

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (α-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation.

Results

In this manuscript, we used the most effective AFFITOPE® (AFF 1) for immunizing MBP-α-syn transgenic mice, a model of MSA that expresses α-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-α-syn antibodies that crossed into the central nervous system and recognized α-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of α-syn involved activation of microglia and reduced spreading of α-syn to astroglial cells.

Conclusions

This study further validates the efficacy of vaccination with AFFITOPEs® for ameliorating the neurodegenerative pathology in synucleinopathies.
Appendix
Available only for authorised users
Literature
1.
Dickson DW, Lin W, Liu WK, Yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol. 1999;9:721–32.CrossRefPubMed
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.CrossRef
3.
4.
Jellinger KA. Neuropathology and pathophysiology of multiple system atrophy. Neuropathol Appl Neurobiol. 2012;38:379–80. author reply 381.CrossRefPubMed
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.CrossRefPubMed
6.
Lee SJ. Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. J Molecular Neuroscie MN. 2008;34:17–22.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
13.
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
18.
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
23.
Schneeberger A, Mandler M, Mattner F, Schmidt W. Vaccination for Parkinson’s disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S11–3.CrossRefPubMed
24.
Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin. 2010;6:948–52.CrossRefPubMed
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.CrossRefPubMed
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.PubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
29.
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.CrossRefPubMed
31.
Muhl H, Pfeilschifter J. Anti-inflammatory properties of pro-inflammatory interferon-gamma. Int Immunopharmacol. 2003;3:1247–55.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
34.
Halliday G. Clinicopathological aspects of motor parkinsonism. Parkinsonism Relat Disord. 2007;13 Suppl 3:S208–10.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
39.
Solomon B. Active immunization against Alzheimer’s beta-amyloid peptide using phage display technology. Vaccine. 2007;25:3053–6.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
44.
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.CrossRefPubMedCentralPubMed
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.CrossRef
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
Metadata
Title
Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy
Authors
Markus Mandler
Elvira Valera
Edward Rockenstein
Michael Mante
Harald Weninger
Christina Patrick
Anthony Adame
Sabine Schmidhuber
Radmila Santic
Achim Schneeberger
Walter Schmidt
Frank Mattner
Eliezer Masliah
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0008-9

Other articles of this Issue 1/2015

Molecular Neurodegeneration 1/2015 Go to the issue

Research article

A brain-targeted, modified neurosin (kallikrein-6) reduces α-synuclein accumulation in a mouse model of multiple system atrophy

Research article

Glutaminase-containing microvesicles from HIV-1-infected macrophages and immune-activated microglia induce neurotoxicity

Review

TREM2 in CNS homeostasis and neurodegenerative disease

Research article

STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity

Research article

APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice

Research article

Synaptotagmins interact with APP and promote Aβ generation