NLRP3 INFLAMMASOME AND DIETARY HABITS IN PARKINSON'S DISEASE: INSIGHTS INTO THE BODY-FIRST HYPOTHESIS

Parkinson disease (PD) is the second most prevalent neurodegenerative disorder, and in various experimental models of PD, a selective loss of dopaminergic neurons is associated with chronic neuroinflammation, partly mediated by microglia, the resident immune cells in the brain. In this setting, a pivotal role has covered by NLRP3 inflammasome, which is a multi-protein complex capable of initiating inflammation in response to cellular stress, including PD-associate factors such as reactive oxygen species and pathologically misfolded proteins. Several studies indicated that among factors associated with risk of developing PD, dietary habits have an important role. Indeed, high-fat diet (HFD) consumption is associated with an increased risk of developing neurological disorders such as depression major and Alzheimer, and this effect seems to be related to obesity-induced inflammation. For this reason, the present study is aimed to determine the role of gut-brain axis and NLRP3 inflammasome in the PD pathogenesis: to investigate if an inflammation driven by obesity could anticipate/exacerbate the pathological features of PD, and if the loss of NLRP3 inflammasome counteracts the effects caused by HFD intake and neurodegenerative process in PD. For this reason, C57BL/6J wild type (WT) mice received oral rotenone (10 mg/Kg) alone or combined to INF176 (1,25 mg/die) administration for 5 weeks. Oral administration of rotenone in mice, besides the development of characteristics PD features, can develop non-motor symptoms related to gut such as loss of body weight, increasing gut permeability and reduced intestinal transit. In addition, rotenone administration induced NLRP3 inflammasome activation, and as consequence IL-1β release at systemic level. Treatment with INF176, a specific NLRP3 inhibitor not absorbable at intestinal level, attenuated gastrointestinal non-motor symptoms caused by rotenone, prevented neuroinflammation as well as NLRP3 inflammasome activation in brain tissue. Notably, INF176 treated mice did not develop PD features induced by rotenone and were found to have the autophagic pathway preserved. Collectively, our findings highlighted the critical role of intestinal NLRP3 inflammasome activation in mediating both peripheral and central features of PD. To explore specific objectives related to obesity, we used C57BL/6J WT and NLRP3-/- male mice fed with high-fat diet (HFD, 60% of energy from fat) or standard diet (SD,10% of energy from fat) for a period of 9 weeks. Our analyses show that HFD-induced obesity protocol reproduced molecular alterations related to PD in mice midbrain and impaired autophagic pathway. NLRP3 ablation seems to protect from these alterations caused by HFD consumption. Furthermore, we used an in vitro HFD model where human macrophages were exposed to free fatty acid palmitate (PA 100 or 200 µM). PA was internalized by macrophages without inducement of lipotoxycity. Up-regulation of pro-inflammatory cytokines and NLPR3 activation occurred in dose-dependent way. NLRP3 specific inhibition by MCC950 did not affect lipid droplets formation in macrophages but attenuated the inflammation driven by PA exposure. Additionally, in vitro HFD was able to exacerbate the α-synuclein encoding gene SNCA expression in dose-dependent manage, which was attenuated by MCC950 treatment. Together, our findings demonstrated that NLRP3 inflammasome activation contributes to trigger metabolic responses during both, PD and obesity, and can be a promising target from new drugs development.