LAUSR

The damage of locus coeruleus (LC) noradrenergic neurons and associated with norepinephrine (NE) depletion are early events in Parkinson's disease (PD). Previous study showed that LC/NE neurodegeneration exacerbates dopaminergic neurotoxicity and motor deficits. However, whether the damage of LC/NE neurons contributes to non-motor symptoms in PD remain unclear. In this study, LC/NE neurons were pre-lesioned by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) in paraquat and maneb-induced mouse PD model. We found that DSP-4 significantly impaired learning and memory performance in paraquat and maneb-treated mice, although it failed to interfere with constipation and depression-like behaviors. Consistently, DSP-4 treatment increased hippocampal neurodegeneration, synaptic loss, α-synuclein expression and Ser129-phosphorylation in mice treated with these two pesticides. Mechanistically, DSP-4 increased iron content in hippocampus by disrupting the balance of iron release protein ferroportin 1 (Fpn-1) and transferrin receptor (TFR) in paraquat and maneb-treated mice. DSP-4 treatment also exacerbated paraquat and maneb-induced decrease of glutathione peroxidase 4 (GPX4) and glutathione contents as well as increase of lipid peroxidation and expressions of gp91phox and p47phox, two subunits of NADPH oxidase, which are all involved in ferroptosis, in mice. Furthermore, exaggerated microglial activation and M1 polarization were observed in DSP-4 and paraquat and maneb co-treated mice compared with paraquat and maneb alone group. Altogether, our findings revealed a critical role of LC/NE neurodegeneration in mediating learning and memory dysfunction in a two pesticide-induced mouse PD model through ferroptosis and microglia-mediated neuroinflammation, proving novel insights into the pathogenesis of cognitive dysfunction in PD.