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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0142-z) contains supplementary material, which is available to authorized users.

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…AMPK promotes lysosomal biogenesis via increased TFEB activity [102] and activates FOXO3 mediated transcription of proteins necessary for macroautophagy [101]. AMPK is thus well positioned as a pharmacological target to stimulate macroautophagy as a treatment strategy in PD [103]. …”

“…Several studies have successfully used AMPK activating agents to facilitate clearance of αSyn and promote neuronal survival [103]. Overexpression of the stress response protein sestrin2 stimulated macroautophagy, reduced αSyn accumulation, and attenuated cytotoxicity in rotenone treated Mes 23.5 cells [184].…”

“…Similarly, PC12 cells incubated in cell media from αSyn overexpressing cells also had decreased viability and lower AMPK activity, but they could be rescued by activating AMPK with AICAR or metformin [187]. In rats, αSyn overexpression decreased the number of SNc DA neurons, while overexpression of the α subunit of AMPK or AMPK-CA ameliorated neuronal loss and deceased αSyn [188]. Likewise, αSyn overexpression in retinoic acid differentiated SH-SY5Y cells increased cell death and decreased AMPK activity [187].…”

“…The neuroprotective effects of AMPK activators, such as metformin, appear to have a narrow effective dose ranges in both in vivo and in vitro models [171,204]. There is evidence from studies in mice that a chronic low level of AMPK activity may be most beneficial [188]. Furthermore, the therapeutic efficacy of AMPK activation may depend on the stage and severity of PD.…”

“…Furthermore, the therapeutic efficacy of AMPK activation may depend on the stage and severity of PD. Several researchers have suggested that AMPK could be neuroprotective during the early stages of PD, but become less effective or potentially detrimental during more progressed stages of the disease [181,188,205]. …”