Advanced age and lipopolysaccharide influence behavioral and neurodegenerative features in LRRK2 G2019S knock-in mice

Parkinson's disease (PD) is a progressive neurodegenerative disease thought to arise from the collective impact of advancing age, genetic vulnerabilities and possibly exposure to environmental toxicants. The LRRK2 point mutation, G2019S, is the most common genetic link with PD and has been reported to have age-dependent effects in rodents, as well as being linked to neuroinflammatory processes. Accordingly, the objective of the current study was to elucidate the interactive effects of advanced age and activation of the immune system using the bacterial endotoxin, lipopolysaccharide (LPS), in G2019S knockin mice and their wild type littermates. Adult young (3-4 months) and aged (9-12 months) mice were administered five intraperitoneal injections of 250 ug/kg of LPS (or saline) every alternate day. Significant interactions between age, genotype and injection were evident across several behavioral outcomes. In fact, the aged G2019S mice were more vulnerable to the LPS injections in terms of the sickness response, deficits in nest building behaviors, weight loss, along with protracted reductions in home cage motor activity. These mice also exhibited alterations of SNc inflammatory microglia proteins (WAVE2 and CXCR1) and had the greatest loss of substantia nigra dopamine neurons, which is consistent with a PD-like phenotype. Taken together, our data suggest that the LRRK2 G2019S mutation might be a general regulator of aging and inflammatory processes that are important for neurodegeneration, together with motor and non-motor symptoms.