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.
Bibliographical noteFunding 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.