Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease.
Abnormal folding of alpha-synuclein (alpha-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)alpha-syn might have therapeutic effects in LBD. For this purpose, halpha-syn transgenic (tg) mice were vaccinated with halpha-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated halpha-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Furthermore, antibodies produced by immunized mice recognized abnormal halpha-syn associated with the neuronal membrane and promoted the degradation of halpha-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged halpha-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of halpha-syn aggregates and that further development of this approach might have a potential role in the treatment of LBD.
Masliah
Eliezer
E
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. emasliah@ucsd.edu
Rockenstein
Edward
E
Adame
Anthony
A
Alford
Michael
M
Crews
Leslie
L
Hashimoto
Makoto
M
Seubert
Peter
P
Lee
Michael
M
Goldstein
Jason
J
Chilcote
Tamie
T
Games
Dora
D
Schenk
Dale
D
D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000627:therapeutic use; D015153:Blotting, Western / Q000379:methods; D002402:Cathepsin D / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D004195:Disease Models, Animal; D018604:Epitope Mapping / Q000379:methods; D006801:Humans; D007114:Immunization / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D002479:Inclusion Bodies / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D017729:Presynaptic Terminals / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D000906:Antibodies; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D016708:Synaptophysin; D051843:Synucleins; D051844:alpha-Synuclein; D002402:Cathepsin D