α-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded α-Synuclein and Neurodegeneration

Accumulation of misfolded alpha-synuclein (alpha-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous alpha-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological alpha-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that alpha-syn monoclonal antibodies (mAbs) reducea-syn pff-inducedLB/LNformationandrescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded alpha-syn into nontransgenic mice injected intrastriatally with alpha-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that alpha-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological alpha-syn and/or its propagation in neurons.