Targeting the JAK/STAT Pathway in the Treatment of Parkinson’s Disease (THER6P.847)

Abstract Parkinson’s Disease (PD) is an age-related, chronic neurodegenerative disorder. At present, there are no therapies to prevent PD progression. Activated microglia and subsequent neuroinflammation associate with the pathogenesis and progression of PD. Accumulation of α-synuclein (α-syn) in the brain is a core feature of PD and leads to microglial activation, inflammatory cytokines/chemokines production and neurodegeneration. Given the importance of the JAK/STAT pathway in activating microglia and inducing cytokine/chemokine expression, we investigated the therapeutic potential of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480. We utilized an in vivo rat model of PD induced by viral overexpression of α-syn. We find that AZD1480 treatment inhibits α-syn-induced neuroinflammation by inhibiting microglia activation and CD3+ T-cell infiltration, and neurodegeneration by preventing the degeneration of dopaminergic neurons in vivo. In vitro, AZD1480 inhibits α-syn- and IFN-γ-induced MHC Class II, CD40, iNOS, TNF-α and IL-6 expression in microglia and macrophages by reducing STAT1 and STAT3 activation. These results indicate that inhibiting the JAK/STAT pathway can prevent neuroinflammation and neurodegeneration by suppressing activation of innate and adaptive immune responses to α-syn and inflammatory cytokines in this PD model. Furthermore, this suggests the feasibility of targeting the JAK/STAT pathway as neuroprotective therapy for neurodegenerative diseases.