Die Rolle der SK-Kanäle in alpha-Synuclein-aktivierter primärer Mikroglia

Hintergrund: Die Parkinson-Erkrankung gehört zu den weltweit häufigsten neurodegenerati-ven Krankheiten und ist die häufigste Bewegungsstörung beim Menschen. In der jüngeren Vergangenheit wurde α-Synuclein als möglicher Auslöser der Parkinsonkrankheit identifiziert. Seit einigen Jahren wird die Roll...

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Bibliographic Details
Main Author: Wilhelmy, Florian
Contributors: Culmsee, Carsten (Prof.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2019
Online Access:PDF Full Text
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Background: Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and the most common movement disorder in the human. α-Synuclein has recently been discovered as a harmful endogenous compound and trigger of PD. The role of microglia in neurodegenerative disorders is an emerging field of research. In fact, increasing evidence suggests that microglia largely contribute to the inflammatory pathogenesis of neurodegenerative diseases. Hypothesis: Previous studies showed that positive modulation of SK-channels by CyPPA significantly inhibited microglial inflammatory responses to LPS. The present study addressed the question, whether similar effects of CyPPA could be observed in α-synuclein-activated microglia. α-synuclein induced microglial proliferation and concomitant pro-inflammatory activation should be modified by CyPPA as judged at the level of morphology, proliferation and the enhanced production of pro-inflammatory cytokines. Methods: We cultivated primary microglia from postnatal mice. These cells where subsequently treated with α-synuclein to induce an inflammatory response. Proliferation was measured using life impedance measurements and visualised via microscopic immunofluorescence imaging. Cytokine production (IL-6, IL1β, TNF-α) was evaluated to assess microglial pro-inflammatory responses. Secondly, pre-, co- and post-treatment of activated cells with CyPPA was performed. The alterations of the pro-inflammatory response of the primary microglial cells to α-synuclein exposure were analyzed at the levels of morphology, proliferation and cytokine expression pattern. Results: Selective opening of SK-channels by CyPPA leads to a significant decrease of inflam-matory responses in microglia exposed to α-synuclein in vitro. This pharmacological effect was observed unequivocally at the levels of proliferation, morphological alterations and expression of pro-inflammatory cytokines. Furthermore we established α-synuclein activation of microglia as a model system for Inflammation in PD. Conclusion: SK-channel modulators are capable of modifying the inflammatory responses of cultured microglia after being activated with α-synuclein. If this effect persisted in co-culture models reducing inflammatory activation of microglia and according damage to primary neu-rons, SK-channels might be a potential pharmaceutical target in treating α-synuclein-induced neuropathological disorders such as Parkinson’s disease.