Publikationsserver der Universitätsbibliothek Marburg

Titel:Pathogenetischer Synergismus von Gen und Umwelt: Einflüsse auf die Tau-Pathologie im FTDP-17-Mausmodell
Autor:Müßner, Stefanie
Weitere Beteiligte: Oertel, Wolfgang (Prof. Dr. med. Dr. h.c.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0023
DOI: https://doi.org/10.17192/z2017.0023
URN: urn:nbn:de:hebis:04-z2017-00236
DDC: Medizin
Titel (trans.):Pathogenetic synergism of genes and environment: influences on tau pathology in a FTDP-17 mouse model
Publikationsdatum:2017-01-23
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Umweltgift, Tauopathie, Microtubule-associated protein tau, Demenz, Mikrotubuli-assoziiertes Protein Tau, Neurodegeneration, Phosphorylierung, Neurodegeneration, Environmental neurotoxin, Tauopathy, Mikrotubulus

Zusammenfassung:
Auf der Suche nach Interaktionen zwischen Genen und Umwelt, die zu einem pathogenetischen Synergismus führen, wurden in dieser Arbeit die neuropathologischen Effekte einer in vivo-Intoxikation mit dem prototypischen Komplex I-Inhibitor Annonacin im transgenen FTDP-17-Mausmodell untersucht. Ziel der Arbeit war es, zu überprüfen, ob Annonacin in vivo zu einer neuronalen Akkumulation von hyperphosphoryliertem Tau, dem charakteristischen Merkmal der FTDP-17 und anderer Tauopathien, führt. Des Weiteren sollte geklärt werden, ob die beobachteten Effekte des Annonacins durch das Vorliegen einer Genmutation verstärkt werden und mit neuronalem Zellverlust und Astrogliose einhergehen. Zur Klärung der Fragestellung wurden Mäuse, die die längste humane Tau-Isoform mit der R406W-Punktmutation exprimieren, sowie Wildtyp-Mäuse über drei Tage mittels subkutan implantierter Minipumpen mit Annonacin (6 mg/kg/d oder 9 mg/kg/d) oder einer Trägerlösung behandelt. Im Anschluss erfolgte die immunhistochemische Darstellung von phosphoryliertem Tau, sowie von Neuronen und Gliazellen im Hirngewebe der Tiere. Mittels stereologischer Methoden und optischer Dichtemessung wurden die Neurone und Gliazellen in verschiedenen Hirnregionen (Frontalcortex, Parietalcortex, Hippocampus und Amygdala) quantifiziert. Bereits unter alleiniger Expression des Transgens konnte im Vergleich zum Wildtyp eine somatodendritische Akkumulation von hyperphosphoryliertem Tau in allen untersuchten Hirnregionen nachgewiesen werden. Es konnte weiterhin gezeigt werden, dass die Akkumulation von hyperphosphoryliertem Tau in den R406W+/+-Tieren unter Annonacinexposition konzentrationsabhängig zunimmt, während in den R406W-/--Tieren kein Unterschied nachweisbar ist. Diese Zunahme der Tau-Pathologie ließ sich im Frontalcortex- und Parietalcortex anhand einer Zunahme Phospho-Tau positiver Neurone und im Hippocampus anhand einer vermehrten optischen Dichte dieser Neurone in der CA2/3-Region nachweisen. Die Quantifizierung Tau-positiver Neurone in der Amygdala ergab jedoch keinen Unterschied zwischen den Behandlungsgruppen. Die immunhistochemische Darstellung der Neurone mittels NeuN-Antikörpern konnte eine signifikant niedrigere Neuronenzahl in allen untersuchten Hirnregionen der R406W+/+-Tiere im Vergleich zu den R406W-/--Tieren nachweisen. Die Annonacinbehandlung führte jedoch nicht zu einer signifikanten Veränderung der Neuronenzahl in den Untersuchungsgruppen. Ebenso blieb die Anzahl an Astro- und Mikroglia in transgenen und Wildtyptieren unter Annonacinexposition unverändert. Zusammenfassend konnte in dieser Arbeit gezeigt werden, dass die dreitägige Exposition gegenüber Annonacin ausreicht, um in R406W-transgenen Mäusen eine somatodendritische Akkumulation von hyperphosphoryliertem Tau zu induzieren, die in Abhängigkeit von der Annonacindosis zunimmt. Dies zeigt exemplarisch, dass ein Umwelttoxin in der Lage ist, den genetisch determinierten Verlauf einer Tauopathie zu verändern, indem es synergistisch mit dem Gendefekt die Taupathologie verstärkt. Die Erforschung der Relevanz weiterer, global verbreiteter Umwelttoxine in der Genese der Tauopathien sowie der genauen Mechanismen, die zu einer Tau-Pathologie führen, sollte Gegenstand weiterer Studien sein und wird essentiell zum Verständnis der Neuropathogenese und zur Entwicklung therapeutischer und prophylaktischer Strategien in der Behandlung von Tauopathien beitragen. Das hier verwendete FTDP-17-Tiermodell kann zur Beantwortung dieser Fragen in Folgestudien Anwendung finden und so Erkenntnisse liefern, die möglicherweise auch auf andere Tauopathien hereditären oder sporadischen Ursprungs übertragbar sind.

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