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
URN: urn:nbn:de:hebis:04-z2017-00236
DOI: https://doi.org/10.17192/z2017.0023
DDC:610 Medizin, Gesundheit
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:
Mikrotubuli-assoziiertes Protein Tau, Microtubule-associated protein tau, Environmental neurotoxin, Tauopathie, Mikrotubulus, Neurodegeneration, Phosphorylierung, Demenz, Umweltgift, Tauopathy, Neurodegeneration

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.

Summary:
Searching for gene-environment interactions leading to pathogenic synergy, this thesis examines the neuropathological effects of an intoxication with the prototypical complex I inhibitor annonacin in a transgenic FTDP-17 mouse model. This work aimed to test, whether annonacin leads to a neuronal accumulation of hyperphosphorylated tau in vivo, which is the characteristical hallmark of FTDP-17 and other tauopathies. Furthermore it aimed to resolve, whether the interaction of annonacin and a genetic factor leads to an increase in tau pathology and whether treatment with annonacin is accompanied by neuronal death and microglial reaction. To clarify these questions we treated mice overexpressing the longest human tau isoform with the R406W mutation and wildtype mice with annonacin (6 mg/kg/d or 9 mg/kg/d) or vehicle via subcutaneous administration with osmotic mini-pumps for a three-day period. Thereafter immunohistochemical staining of the brain tissue was done with antibodies against phosphorylated tau, neurons and glial cells. Quantification of neurons und glial cells in the different brain regions (frontal and parietal cortex, hippocampus, amygdala) was conducted by stereological cell counting und optical density measurement. In comparison to wildtype mice, the expression of the transgene in R406W+/+ mice was sufficient to cause somatodentritic accumulation of hyperphosphorylated tau. Administration of annonacin led to a dose-dependent increase of somatodentritic phospho-tau accumulation in R406W+/+ mice, while there was no effect in R406W-/- mice. This increase in tau pathology was determined by an increase of phospho-tau positive neurons in the frontal und parietal cortex and by an increased optical density of phospho-tau positive neurons in the CA2/3 region of the hippocampus. In the amygdala, annonacin exposure had no significant additional effect on phospho-tau labeling. Immunohistochemical staining of neurons using the anti-NeuN antibody revealed that there is a significantly lower number of neurons in all brain regions examined in R406W+/+ mice as compared to R406W-/- mice. However annonacin treatment had no significant influence on neuronal numbers in the different treatment groups und genotypes. In the same way, annonacin did not cause significant alteration in the number of microglia or astrocytes of either transgenic or wildtype mice. In summary, this work has shown that a three-day exposure with annonacin is sufficient to cause a dose-dependent increase of somatodentritic accumulation of phospho-tau in R406W-transgenic mice. This demonstrates that an environmental toxin is able to change the course of a tauopathy determined by a genetic factor by increasing tau pathology in synergism with the genetic defect. It should be the aim of further studies to elucidate the relevance of further globally distributed environmental toxins in the pathogenesis of tauopathies as well as the exact mechanisms which lead to tau pathology. This knowledge will be essential for the understanding of the pathogenesis of these diseases and for the development of prophylactic and therapeutic strategies for the treatment of tauopathies. The FTDP-17 mouse model used in this study can be applied in further studies and might give insights, which are relevant not only for FTDP-17 but also for other tauopathies of genetic or sporadic origin.

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