JAK1/2 Inhibitor Suppresses Neuroinflammation in the Thy1 -Syn Mouse Model of Parkinson's Disease

Abstract Parkinson’s Disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons and accumulation of α-synuclein (α-Syn). Targeting the JAK/STAT pathway to treat PD is under investigation due to its roles in inflammatory cytokine production and activation of immune cells. Striatal injection of sonicated human α-Syn pre-formed fibrils (PFF) enhances immune cell infiltration, phosphorylation of α-Syn and MHC Class II expression in the Thy1 α-Syn model (Thy1-PD). We investigated the effect of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480, on neuroinflammation. Immunofluorescence staining showed significantly decreased phosphorylation of α-Syn and MHC Class II expression in Thy1-PD mice after AZD1480 treatment. AZD1480 treatment reduced the infiltration of CD4 +T-cells, CD8 +T-cells, CD19 +B-cells and macrophages into the midbrain compared to vehicle-treated PFF mice, as assessed by flow cytometry. Furthermore, AZD1480 suppressed the infiltration of MHC class II +macrophages and dendritic cells in PFF-injected mice. Importantly, single-cell RNAseq analysis of CD45 +cells identified 9 clusters of microglia, 5 clusters of macrophages and 5 clusters of T-cells, in which specific pathogenic clusters of microglia, macrophages and T-cells are critical for inflammatory responses in Thy1-PD mice. AZD1480 treatment reduced the numbers of the pathogenic clusters, comparable to cell clusters in control monomer/PBS mice. Together, these results suggest inhibiting the JAK/STAT pathway suppresses the infiltration and activation of innate and adaptive cells, thereby reducing the neuroinflammatory response in the Thy1-PD model. This work was supported by grant P50NS108675.