Does Microglial Activation Influence Propagation of Alpha-synuclein Pathology

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 DESCRIPTION (provided by applicant): Neuron-to-neuron propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the stereotypical progression pattern of α-syn neuropathology. This postulate suggests that aggregated α-syn transfers from one neuron to another where it seeds further α-syn aggregation. However, it is not known how microglia influence this process, and how specific microglia activation states that occur upon inflammation affect α-syn transfer. To fill this gap i knowledge we developed a unique mouse model that allows us to monitor α-syn prion-like propagation between neurons. Our in vivo paradigm involves transplantation of embryonic midbrain neurons into the striatum of a mouse overexpressing human α- syn and allows the manipulation of microglia (i.e. ablation or specific activation). In this novel model, the presence of human α-syn within the grafted mouse cells (initially devoid of human α-syn) is used as a read-out for α-syn transfer. Based on our preliminary data we hypothesize that under normal conditions, microglia take up α-syn from the extracellular space, resulting in reduced α-syn transfer from neuron to neuron. We also hypothesize that α-syn accumulates in microglia following lipopolysaccharide treatment, as lipopolysaccharide -activated microglia have reduced proteolytic capacity whereas Interleukin 4-induced microglia effectively reduce the pool of extracellular α-syn, and thereby mitigate α-syn transfer from neuron to neuron. Two specific aims will be pursued to test this hypothesis: 1) Determine how the absence of microglia affects neuron-to-neuron transfer of α-syn; and 2) Determine how the presence of lipopolysaccharide-induced vs Interleukin 4-induced activated microglia affects the rate of neuron-to-neuron transfer of α-syn. First, we will monitor if the absence of microglia results in a different degre of α-syn cell-to-cell transfer using our unique in vivo model of cell-to-cell transfer. Second, we wil assess the transfer of α-syn into grafted neurons in the context of distinct microglial phenotypes lipopolysaccharide or Interleukin 4 injection will be used to stimulate these differential phenotypes. Our approach is innovative because it allows us to assess the interaction between two factors (inflammation and α-syn propagation) both considered to play key roles in PD pathogenesis in a single animal model, and we can define outcomes using unbiased, automated and quantitative measures of neuropathology. We predict that the absence of microglia will translate to increased neuron-to-neuron transfer of α-syn and that the nature of microglial activation will affect the accumulation of α-syn within microglia. Ultimately, the proposed research will result in an innovative and valid model of α-syn pathology propagation with the potential to facilitate the development of disease-modifying therapies based on treatments that modulate inflammation.