Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (alpha-syn). This study investigated whether passive immunization with a novel monoclonal alpha-syn antibody (9E4) against the C-terminus (CT) of alpha-syn was able to cross into the CNS and ameliorate the deficits associated with alpha-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved alpha-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display alpha-syn accumulation and promotes alpha-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of alpha-syn may be of therapeutic relevance in patients with PD and DLB.