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

Background: Cell-to-cell propagation of a-synuclein (a-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of a-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote a-syn aggregation. However, it is unclear how microglia influence a-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor a-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human a-syn (hua-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 hua-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of hua-syn within the grafted cells as a readout. Results: First, we compared a-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 hua-syn in grafted dopaminergic neurons. Second, we assessed the transfer of a-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 and cytokine production) and significantly higher amounts of hua-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained hua-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected a-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of a-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology. Overall design: RNA-seq on mouse striatum injected with PBS, LPS or IL-4