Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn)pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulatemajor histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PDrisk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong linkbetween innate and adaptive immune responses in PD. We have previously reported that reducedlevels of the class II transactivator, the master regulator of MHCII expression, increases susceptibilityto α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of solubleTNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant,XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models,fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combiningrAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils twoweeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observedup to 70% loss of striatal dopaminergic fibers without treatment, and no protective effects ondopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well asmicroglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595,possibly explaining a lack of protective effects following treatment. Our results highlight the need todetermine the importance of timing of treatment initiation, which is crucial for future applications ofsTNF therapies in PD patients.