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

Abstract

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 (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-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 α-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 α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

“…Briefly, cells were grown in glass bottom dishes (MatTek Corporation, Ashland, MA, USA) and then postfixed in 1% glutaraldehyde, treated with osmium tetraoxide, embedded in epon araldite, detached from the glass coverslips and sectioned with the ultramicrotome (Leica, Wetzlar, Germany). Grids were analyzed with a Zeiss (Jena, Germany) OM 10 electron microscope as previously described 40 in order to evaluate the approximate numbers of APs per cell. For morphometric analysis of APs from each section, electron micrographs were obtained at a final magnification of  12 000, and a total of 20 cells were analyzed for each experiment.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Different groups have investigated which region of the α-syn protein is the best target for the development of disease-modifying monoclonal antibodies. We and others have observed that antibodies that recognize an epitope in the C-terminus of α-syn are more effective at ameliorating the pathology in transgenic mouse models of PD, as they clear intracellular aggregates, inhibit α-syn propagation, and prevent C-terminus cleavage of the protein, which may lead to increased aggregation [54,84,120,121]. However, other groups have reported that antibodies against the N-terminus are also effective at clearing α-syn aggregates, reducing their propagation, and diminishing motor dysfunctions [122,123].…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…Antibody-bound aggregates traffic more readily to the lysosomes of microglia, allowing for more effective breakdown and decreased cell-cell transfer of α-synuclein in a transgenic mouse model [109]. Both active and passive immunization against α-synuclein in a transgenic mouse model of PD decreased α-synuclein accumulation and decreased neurodegeneration and functional decline [110,111]. The first vaccination-based treatment for PD is currently in phase I clinical trials.…”