Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Background: Cell-to-cell transmission of a-synuclein (aSyn) is hypothesized to play an important role in disease progression in synucleinopathies. This process involves cellular uptake of extracellular amyloidogenic aSyn seeds followed by seeding of endogenous aSyn. Though it is well known that aSyn is an immunogenic protein that can interact with immune receptors, the role of innate immunity in regulating induction of aSyn pathology in vivo is unknown. Herein, we explored whether altering innate immune activation affects induction of aSyn pathology in wild type mice. Methods: We have previously demonstrated that recombinant adeno-associated virus (AAV) mediated expression of the inflammatory cytokine, Interleukin (IL)-6, in neonatal wild type mice brains leads to widespread immune activation in the brain without overt neurodegeneration. To investigate how IL-6 expression affects induction of aSyn pathology, we injected mouse wild type aSyn fibrils in the hippocampus of AAV-IL-6 expressing mice. Control mice received AAV containing an Empty vector (EV) construct. Two separate cohorts of AAV-IL-6 and AAV-EV mice were analyzed in this study: 4 months or 2 months following intrahippocampal aSyn seeding. Results: Here, we show that IL-6 expression resulted in widespread gliosis and concurrently reduced aSyn inclusion pathology induced by a single intra-hippocampal injection of exogenous amyloidogenic aSyn. The reduction in aSyn inclusion pathology in IL-6 expressing mice was time-dependent. Suppression of aSyn pathology was accompanied by reductions in both argyrophilic and p62 immunoreactive inclusions. Conclusions: Our data supports a beneficial role of inflammatory priming of the CNS in wild type mice challenged with exogenous aSyn. A likely mechanism is efficient astroglial scavenging of exogenous aSyn, at least early in the disease process, and in the absence of human aSyn transgene overexpression. Given evidence that a proinflammatory environment may restrict seeding of aSyn pathology, this can be used to design anti-aSyn immunobiotherapies by harnessing innate immune function.