Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy

Background: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (alpha-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs (R), was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, alpha-syn accumulation and inflammation. Results: In this manuscript, we used the most effective AFFITOPE (R) (AFF 1) for immunizing MBP-alpha-syn transgenic mice, a model of MSA that expresses alpha-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-alpha-syn antibodies that crossed into the central nervous system and recognized alpha-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of alpha-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of alpha-syn involved activation of microglia and reduced spreading of alpha-syn to astroglial cells. Conclusions: This study further validates the efficacy of vaccination with AFFITOPEs (R) for ameliorating the neurodegenerative pathology in synucleinopathies.