C054 - Peripheral LPS-induced inflammation increases the susceptibility for proteasome inhibition-induced degeneration of the nigrostriatal pathway

Neuroinflammation is a common feature in the pathogenesis of Parkinson's disease (PD), together with - among others - oxidative stress, proteasomal and mitochondrial dysfunction. Peripheral inflammation-induced microglial activation has been shown to increase the susceptibility of the brain for nigrostriatal degeneration. The aim of this study is therefore to create a dual-hit mouse model for PD, characterized by lipopolysaccharide (LPS)-induced neuroinflammation prior to nigral proteasome inhibition. To do so, we administered repeated low-dose LPS injections (250µg/kg for 4 days; i.p.) or a single high-dose LPS injection (5mg/kg, i.p.), to induce neuroinflammation. Next, we administered a unilateral intranigral injection of lactacystin (LAC; 3µg), a proteasome inhibitor that acutely induces dopaminergic neurodegeneration. Seven days after administration of LAC, mice were evaluated behaviorally before collecting the brain. Nigrostriatal degeneration was analyzed by quantifying striatal dopamine loss as well as loss of nigral dopaminergic neurons. Presence of neuroinflammation was confirmed by labelling Iba1-positive cells in the substantia nigra (SN). Our results show that systemic LPS injection(s) induce(s) an increase in the number of Iba1-positive cells in the SN, without inducing degeneration of the nigrostriatal pathway. However, LPS-induced neuroinflammation increases the susceptibility for LAC-induced degeneration of the nigrostriatal pathway. This dual-hit model might as such represent a relevant mouse model for PD - combining two pathogenic mechanisms - to be used to investigate the potential of therapeutic targets.