Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is pathologically characterized by loss of dopaminergic neurons from the substantia nigra, the presence of aggregated alpha-synuclein (alpha S) and evidence of neuroinflammation. Experimental studies have shown that the cerebral injection of recombinant fibrillar alpha S, especially in alpha S transgenic mouse models, can induce the formation and spread of alpha S inclusion pathology. However, studies reporting this phenomenon did not consider the presence of lipopolysaccharide (LPS) in the injected alpha S, produced in E. coli, as a potential confound. The objectives of this study are to develop a method to remove the LPS contamination and investigate the differences in pathologies induced by alpha S containing LPS or alpha S highly purified of LPS. Results and conclusions: We were able to remove >99.5 % of the LPS contamination from the alpha S preparations through the addition of a cation exchange step during purification. The alpha S pathology induced by injection of fibrils produced from alpha S containing LPS or purified of LPS, showed a similar distribution pattern; however, there was less spread into the cortex of the mice injected with alpha S containing higher levels of LPS. As previously reported, injection of alpha S fibrils could induce astrogliosis, and aS inclusions were present within astrocytes in mice injected with fibrils comprised of alpha S with or without cation exchange purification. Furthermore, we identified the presence of alpha S pathology in ependymal cells in both groups of mice, which suggests the involvement of a novel mechanism for spread in this model of alpha S pathology.