Abstract
Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid / metabolism
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Amyloid / ultrastructure
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Analysis of Variance
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Animals
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Antibodies / metabolism
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Antibodies / pharmacology*
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Antigens, CD / metabolism
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Astrocytes / metabolism
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Brain / metabolism
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Brain / pathology
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Calcium-Binding Proteins / metabolism
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Cathepsin D / metabolism
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Caveolin 1 / metabolism
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Cell Communication / physiology
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Cell Line
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Chromatography, Gel
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Culture Media, Conditioned / pharmacology
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Cytokines / metabolism
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Disease Models, Animal
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Extracellular Space / drug effects
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Extracellular Space / immunology
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Extracellular Space / metabolism
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Humans
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Immunization, Passive
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Lewy Body Disease / genetics
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Lewy Body Disease / immunology
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Lewy Body Disease / metabolism
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Mice
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Mice, Transgenic
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Microfilament Proteins / metabolism
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Microscopy, Electron, Transmission
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Nerve Degeneration / drug therapy
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Nerve Degeneration / genetics
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Nerve Degeneration / immunology
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Neuroglia / drug effects*
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Neuroglia / metabolism
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Phosphopyruvate Hydratase / metabolism
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Platelet-Derived Growth Factor / metabolism
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Synaptic Transmission / physiology
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alpha-Synuclein / genetics
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alpha-Synuclein / immunology*
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alpha-Synuclein / metabolism*
Substances
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Aif1 protein, mouse
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Amyloid
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Antibodies
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Antigens, CD
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Calcium-Binding Proteins
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Caveolin 1
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Culture Media, Conditioned
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Cytokines
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Microfilament Proteins
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Platelet-Derived Growth Factor
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alpha-Synuclein
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Cathepsin D
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Phosphopyruvate Hydratase