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Abstract

Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson’s disease (PD). Researchers have shown that Fibroblast growth factor21 (FGF21) plays multiple biological functions including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In the current study, both in vivo and in vitro models were used to investigate whether FGF21 enhances brain function through modulating microglia polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mice model alongside intraperitoneally received FGF21. A battery of behavioral tests and Tyrosine-hydroxylase (TH) immunohistochemistry were conducted to evaluate neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western Blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in PD mice. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed microglial M1 polarization and the subsequent mRNA expression of proinflammatory factors, while promoting M2 microglia polarization with increasing anti-inflammatory factors in PD mice. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21 induced microglial M2 polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21 induced SIRT1 expression and microglia M2 polarization. Moreover, FGF21 pre-treatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in PD pathology through SIRT1/NF-κB pathway mediated microglial polarization. Given the safety record of human clinical trials，FGF21 could be a promising therapy for clinical trials to ameliorate motor and non-motor deficits in PD patients.