Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson's disease

Background Cell-to-cell propagation of alpha-synuclein (alpha-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of alpha-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote alpha-syn aggregation. However, it is unclear how microglia influence alpha-syn cell-to-cell transfer. Methods We developed a clinically relevant mouse model to monitor alpha-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human alpha-syn (hu alpha-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of hu alpha-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of hu alpha-syn within the grafted cells as a readout. Results First, we compared alpha-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of hu alpha-syn in grafted dopaminergic neurons. Second, we assessed the transfer of alpha-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology, cytokine production and an upregulation in genes involved in the inflammatory response in the LPS-injected mice by RNA sequencing analysis). LPS-injected mice had significantly higher amounts of hu alpha-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained hu alpha-syn relative to controls. As expected, RNA sequencing analysis on striatal tissue revealed differential gene expression between LPS and IL-4-injected mice; with the genes upregulated in tissue from mice injected with LPS including several of those involved in an inflammatory response. Conclusions The absence or the hyperstimulation of microglia affected alpha-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of alpha-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.