Title |
Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials
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Published in |
Acta Neuropathologica, February 2014
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DOI | 10.1007/s00401-014-1256-4 |
Pubmed ID | |
Authors |
Markus Mandler, Elvira Valera, Edward Rockenstein, Harald Weninger, Christina Patrick, Anthony Adame, Radmila Santic, Stefanie Meindl, Benjamin Vigl, Oskar Smrzka, Achim Schneeberger, Frank Mattner, Eliezer Masliah |
Abstract |
Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs(®) (AFF)- that do not elicit an α-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson's disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 2 | <1% |
Unknown | 210 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 32 | 15% |
Researcher | 30 | 14% |
Student > Master | 29 | 14% |
Student > Ph. D. Student | 27 | 13% |
Student > Doctoral Student | 13 | 6% |
Other | 31 | 15% |
Unknown | 50 | 24% |
Readers by discipline | Count | As % |
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Neuroscience | 38 | 18% |
Medicine and Dentistry | 30 | 14% |
Biochemistry, Genetics and Molecular Biology | 29 | 14% |
Agricultural and Biological Sciences | 20 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 5% |
Other | 24 | 11% |
Unknown | 61 | 29% |