Publikationsserver der Universitätsbibliothek Marburg
Titel:Wirkmechanismen des MAP-Kinase Inhibitors CNI-1493 auf mikrogliale BV-2 Zellen und primäre Mikroglia
Autor:Mengel, David
Weitere Beteiligte: Dodel, Richard (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0329
DOI: https://doi.org/10.17192/z2013.0329
URN: urn:nbn:de:hebis:04-z2013-03293
DDC: Medizin
Titel (trans.):Mechanisms of action of the MAP-kinase inhibitor CNI-1493 with respect to BV-2 cells and primary microglia
Publikationsdatum:2013-06-26
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Alzheimer-Disease, Alzheimer-Krankheit, Mikroglia, Microglia

Zusammenfassung:
Ein zentrales Merkmal der Demenz vom Alzheimertyp (AD) ist die Akkumulation von β-Amyloid-Oligomeren sowie die Ausbildung einer β-Amyloid-induzierten Entzündungsreaktion im Gehirn. β-Amyloid entsteht aus einem Vorläuferprotein, dem APP, welches durch Sekretasen prozessiert wird. Die Bildung und der Abbau dieser Oligomere stellen einen zentralen Ansatz in der Entwicklung neuer Medikamente für AD dar. Insbesondere wird versucht, die Sekretasenaktivität zu beeinflussen, den Abbau von β-Amyloid zu fördern, die Aggregation von β-Amyloid zu hemmen sowie die durch die Oligomere bedingte Toxizität zu beeinflussen. Darüber hinaus steht die Modulation der β-Amyloid-induzierten Inflammation, bei der es zu einer starken Aktivierung mikroglialer Zellen kommt, im Focus des Interesses. In diesem Zusammenhang konnte gezeigt werden, dass der entzündungshemmende p38 MAPK Hemmstoff CNI-1493 in einem transgenen Mausmodel der Demenz vom Alzheimertyp zu einer deutlichen Reduktion der intrazerebralen β-Amyloid-Konzentration und gleichzeitig zu einer Verbesserung der Kognition dieser Tiere geführt hat. Allerdings sind die Wirk-mechanismen dieser Substanz nicht vollständig geklärt. Auch die besondere Wirkung auf die Mikroglia, einer zentralen Zelle bei der Erkrankung, ist noch unklar. Daher war das Ziel der vorliegenden Arbeit, zum einem die Interaktion zwischen CNI-1493 und β-Amyloid zu charakterisieren. Weiterhin wurde in vitro an primären Mikrogliazellen der Einfluss von CNI-1493 auf die Zytokinsekretion, die Aktivität der Sekretasen, die Toxizität von β-Amyloid und die Phagozytosefähigkeit untersucht. Primäre Mikroglia wurden aus Mesokortizes von Mausembryonen isoliert. Zusätzlich erfolgten die ersten Experimente an einer Zellkulturlinie. Zur Untersuchung der Zytotoxizität wurden MTT-Assays durchgeführt. Die Sekretion von Zytokinen und Amyloid-β wurde mit Hilfe von ELISAs untersucht. Die Fähigkeit der Zellen zur Phagozytose wurde durch FACS-Analysen überprüft. Die Interaktion zwischen CNI-1493 und β-Amyloid-Oligomeren wurde anhand von Westernblot bzw. Dot-Blot-Verfahren getestet. Die Aktivität der Sekretasen wurde indirekt durch RT-PCR dargestellt, während deren Funktion mit Hilfe von fluoro-metrischen Assays bestimmt wurde. Wir konnten zeigen, dass CNI-1493 in der Lage ist, die Bildung von toxischen Aggregations-formen des β-Amyloids zu hemmen. Dadurch ließ sich die β-Amyloid-induzierte Schädigung mikroglialer Zellen reduzieren. Auch die Sekretion von proinflammatorischen Zytokinen konnte durch CNI-1493 vermindert werden. Darüber hinaus ließ sich durch die Inkubation mit CNI-1493 die Phagozytose von β-Amyloid verbessern. Wir konnten auch zeigen, dass CNI-1493 die Funktion der α-Sekretase moduliert und dadurch die Induktion des nicht-amyloidogenen Weges der APP-Prozessierung induziert. In der vorliegenden Studie konnten wir relevante Wirkmechanismen von CNI-1493 in der mikroglialen Zellkultur aufklären. Unsere Daten zeigen, dass es nicht nur zu einem direkten Effekt von CNI-1493 auf Bildung toxischer β-Amyloid-Oligomere kommt, sondern über eine Inhibition des p38 MAPK Signalweges auch zur Modulation immunologischer Funktionen von mikroglialen Zellen. Über eine Aktivierung der α-Sekretase durch CNI-1493 ließ sich zudem eine Reduktion der β-Amyloid-Sekretion mikroglialer Zellen induzieren. In der Zusammen-schau dieser Ergebnisse scheint diese Substanz gerade aufgrund der unterschiedlichen Wirk-mechanismen für eine Therapie der AD geeignet. Berücksichtigt man die Tatsache, dass CNI-1493 bereits erfolgreich in einer klinischen Studie bei M. Crohn getestet wurde, wäre der Einsatz in einer klinischen Studie bei Patienten mit AD möglich.

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