Effects of α-synuclein immunization in a mouse model of Parkinson's disease

Eliezer Masliah, Edward Rockenstein, Anthony Adame, Michael Alford, Leslie Crews, Makoto Hashimoto, Peter Seubert, Michael Lee, Jason Goldstein, Tamie Chilcote, Dora Games, Dale Schenk

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410 Scopus citations

Abstract

Abnormal folding of α-synuclein (α-syn) is thought to lead to neurodegeneration and the characteristic symptoms of Lewy body disease (LBD). Since previous studies suggest that immunization might be a potential therapy for Alzheimer's disease, we hypothesized that immunization with human (h)α-syn might have therapeutic effects in LBD. For this purpose, hα-syn transgenic (tg) mice were vaccinated with hα-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated hα-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Furthermore, antibodies produced by immunized mice recognized abnormal hα-syn associated with the neuronal membrane and promoted the degradation of hα-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged hα-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of hα-syn aggregates and that further development of this approach might have a potential role in the treatment of LBD.

Original languageEnglish (US)
Pages (from-to)857-868
Number of pages12
JournalNeuron
Volume46
Issue number6
DOIs
StatePublished - Jun 16 2005

Bibliographical note

Funding Information:
This work was supported by NIH grants AG18440, AG5131, and AG022074 and a grant from Elan Pharmaceuticals. The authors wish to thank Jiping Huang and Robin Barbour (Elan Pharmaceuticals) for preparation of the anti-hα-synuclein 9E4 antibody.

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