The effects of soluble TNF inhibition in an a-Synuclein seeded rat model for Parkinsons disease

FILIP BACKSTROM; OLIVIA TRUJEQUE; JOAQUIN PARDO; MALÚ TANSEY; MARIA SWANBERG

Leuven

Congreso; Periphery-brain Interplay and CNS Disease; 2023

Major histocompatibility complex II (MHCII) expression is controlled by the class II transactivator (CIITA). We have previously shown using congenic rats that DA.VRA4 rats with lower CIITA and MHCII levels (~60% and ~80% reduction, respectively) have more phenotypically activated microglia after a-Synuclein (a-Syn) overexpression in the substantia nigra (SN) and more severe neurodegeneration compared to wildtype DA rats. Additionally, DA.VRA4 rats had more widespread a-Syn pathology after nigral overexpression of a-Syn combined with striatal seeding with human a-Syn pre-formed fibrils (PFFs). In an ongoing study using recombinant adeno-associated viral vector (rAAV)-mediated overexpression of human a-Syn in SN combined with striatal seeding with PFFs to model PD we have seen that DA.VRA4 rats have higher levels of soluble tumor necrosis factor alpha (sTNF) in serum. We hypothesize that the increased levels of sTNF are associated with the increased susceptibility and progression of PD-like neurodegeneration and pathology observed in DA.VRA4 rats. Therefore, we aimed to evaluate the effects of a dominant-negative sTNF inhibitor using the same unilateral rAAV/PFF PD model described above. In this study, DA.VRA4 rats were subcutaneously injected with the sTNF inhibitor every third day for a total of 7 weeks prior to euthanasia. Cytokine levels in cerebrospinal fluid and blood samples are analyzed by ELISA and dopaminergic neurodegeneration, a-Syn pathology, microglia and astrocyte response are analyzed by immunohistochemistry.