Differential susceptibility to inflammation and neurodegeneration in two models of aged rats.

RODOLFO TARELLI; FERNANDO PITOSSI; ESTEBAN MIGLIETTA; CARINA FERRARI; MARÍA ISABEL FARÍAS

Mar del Plata

Congreso; Ruenión anual SAIC-SAFE-SAB-SAP 2019; 2019

SAIC

Parkinson?s Disease (PD) is a neurodegenerative disorder whose main feature is the neuronal loss in the substantia nigra (SN). Our group and others have demonstrated that inflammation can cause or exacerbate neuronal demise in the SN, suggesting that the modulation of inflammation could be a possible site of therapeutic intervention. Several factors can influence the development of PD. Age is the most relevant risk factor for this disease. Also, a mutation (G2019S) in the LRRK-2 gene is the most prevalent mutation in PD patients. Interestingly, aged animals and animals carrying a LRRK-2 (G2019S) mutated gene produce an increased response to inflammatory stimuli when compared with adult animals. Therefore, we hypothesize that aged animals expressing LRRK-2 (G2019S) show an increased inflammatory response and therefore a higher risk for neurodegeneration in the SN. To test the hypothesis, aged rats (12-18 months) were inoculated in the SN with adenoviral vectors expressing LRRK-2(G2019S) or eGFP (control). 21 days later, all animals were intravenously injectedwith adenoviral vectors expressing Interleukin-1b (AdIL-1b), causing inflammation. In the aged LRRK-2 (G2019S)/AdIL-1b animals, a marked increase in microglia activation but no signs ofneurodegeneration or motor symptoms were detected. In parallel, aged rats injected with a subtoxic dose of 6-OHDA or vehicle were challenged with peripheral AdIL-1b or an adenovirus expressing betagalactosidase. Only 6-OHDA/AdIL-1 animals showed signs of neurodegeneration (28.44 %) with 2-fold increase in microglia activation and no differences in astrogliosis. We conclude that although both models showed increased microglial activation, nigral degeneration was observed in 6-OHDA-treated but not in LRRK-2 (G2019S)-expressing aged rats, suggesting different mechanisms of nigral susceptibility to inflammation in both models. These data set the basis to identify molecules of inflammation-mediated neuronal demise in aged animals.