Abstract
BackgroundCell-to-cell transmission of α-synuclein (αSyn) is hypothesized to play an important role in disease progression in synucleinopathies. This process involves cellular uptake of extracellular amyloidogenic αSyn seeds followed by seeding of endogenous αSyn. Though it is well known that αSyn is an immunogenic protein that can interact with immune receptors, the role of innate immunity in regulating induction of αSyn pathology in vivo is unknown. Herein, we explored whether altering innate immune activation affects induction of αSyn pathology in wild type mice.MethodsWe 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 αSyn pathology, we injected mouse wild type αSyn 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 αSyn seeding.ResultsHere, we show that IL-6 expression resulted in widespread gliosis and concurrently reduced αSyn inclusion pathology induced by a single intra-hippocampal injection of exogenous amyloidogenic αSyn. The reduction in αSyn inclusion pathology in IL-6 expressing mice was time-dependent. Suppression of αSyn pathology was accompanied by reductions in both argyrophilic and p62 immunoreactive inclusions.ConclusionsOur data supports a beneficial role of inflammatory priming of the CNS in wild type mice challenged with exogenous αSyn. A likely mechanism is efficient astroglial scavenging of exogenous αSyn, at least early in the disease process, and in the absence of human αSyn transgene overexpression. Given evidence that a pro-inflammatory environment may restrict seeding of αSyn pathology, this can be used to design anti-αSyn immunobiotherapies by harnessing innate immune function.
Highlights
Cell-to-cell transmission of α-synuclein is hypothesized to play an important role in disease progression in synucleinopathies
The observations that innate immune activation is an invariant finding in synucleinopathies and that αSyn, by itself, can directly interact with immune cells suggest that innate immunity can potentially modify how exogenous αSyn is able to influence the onset and progression of α-synucleinopathy
Using recombinant adeno-associated viruses overexpressing IL-6 in the brains of wild type mice [33], we explored how preconditioning innate immune milieu in the Central nervous system (CNS) affects the induction of αSyn pathology following challenge with exogenous aggregated αSyn
Summary
Cell-to-cell transmission of α-synuclein (αSyn) is hypothesized to play an important role in disease progression in synucleinopathies. The aberrant aggregation of αSyn to form amyloidogenic inclusions is thought to follow a prion-like mechanism involving the molecular conversion of protein monomers from their predominantly unfolded structure to a β-pleated sheet that can polymerize into amyloid (reviewed in [4]). CNS resident astrocytes as well as macrophages can endocytose αSyn via dynamin-related pathways [16, 17], suggesting that immune pathways can potentially have disease modifying effects in α-synucleinopathies
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