Impact of aging on the central and enteric nervous system in a Parkinson's Disease Mouse Model

Solène Pradeloux^1,2Maélie Fréchette²Mathilde Drolet²Catherine Fontaine-Lavallée¹Mélissa Côté^1,2Katherine Coulombe^1,2Marie Rieux¹Frederic Calon^1,2Denis Soulet^1,2*

• ¹Centre de Recherche du CHU de Québec, Québec City, Quebec, Canada
• ²Faculté de Pharmacie, Laval University, Quebec, Canada

The etiopathogenesis of Parkinson's Disease (PD) remain poorly understood, particularly the roles of aging and the gut-brain axis. This study investigated the impact of aging on the development of PD hallmarks, including neurodegeneration and inflammation, in both the central (CNS) and enteric (ENS) nervous system of mice following exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Young (2-4 months) and adult (7-12 months) mice were treated with either saline or MPTP (four intraperitoneal injections of 8 mg/kg at 2-hour intervals). Postmortem inflammatory and neuronal endpoints were compared in both the nigrostriatal pathway and the myenteric plexus. While age did not alter the MPTP-induced reduction in TH-positive cells in the striatum and substantia nigra pars compacta (SNpc), we observed a greater sensitivity of enteric DAergic neurons to MPTP neurotoxicity with age. Notably, MPTP treatment elicited a more prominent inflammatory response in the SNpc and the myenteric plexus in older animals, as assessed with Iba1 and GFAP immunofluorescence on brain sections. We also observed enteric and central inflammation, an increase in oxidative stress in the SNpc measured with Nrf2, and a loss of enteric DAergic neurons with aging, comparable to what is observed in young mice treated with MPTP. The enhanced vulnerability of the ENS is consistent with the observation that intestinal symptoms precede motor symptoms in PD, suggesting that immunosenescence in the gastrointestinal tract contributes to the early development and progression of PD.