Antibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission

Abnormal deposition and intercellular propagation of alpha-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 alpha-synuclein resulted in reduced alpha-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 alpha-synuclein specifically target and aid in clearance of extracellular alpha-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fc gamma receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of alpha-synuclein tg mice prevented neuron-to-astroglia transmission of alpha-synuclein and led to increased localization of alpha-synuclein and the antibody in microglia. Furthermore, passive immunization with alpha-synuclein antibody reduced neuronal and glial accumulation of alpha-synuclein and ameliorated neurodegeneration and behavioral deficits associated with alpha-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of alpha-synuclein as potential therapeutic targets.