Publikationsserver der Universitätsbibliothek Marburg

Titel:Alzheimer’s disease: Amyloid oligomers, therapeutic agents, their target and mode of action
Autor:Balakrishnan, Karthikeyan
Weitere Beteiligte: Bacher, Michael (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0007
URN: urn:nbn:de:hebis:04-z2013-00078
DOI: https://doi.org/10.17192/z2013.0007
DDC:610 Medizin
Titel (trans.):Alzheimer Krankheit: Amyloid Oligomere, therapeutische Agentien, ihre Angriffsziele und Wirkmechanismus
Publikationsdatum:2013-01-29
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Epitope characterization, Morbus Alzheimer, Naturally occurring autoantibodies, AD immunotherapy, Antikörper, Amyloid beta, Oligomere, Amyloid oligomer-specific autoantibodies, Nichtsteroidales Antiphlogistikum

Summary:
Das umfassende Ziel dieser Arbeit ist es die Effekte von natürlich vorkommenden Autoantikörpern (Nabs) und CNI-1493 (immunmodulatorische Substanz) auf Amyloid-beta (Aβ) Oligomere zu beschreiben. Die extrazelluläre Anreicherung von Aβ im Gehirn steht im Verdacht Ursache und Auslöser der Alzheimer’schen Demenz (AD) zu sein. Die genaue physiologische Rolle von Aβ ist jedoch unklar. Jüngere Ergebnisse zeigen dass monomeres Aβ an der normalern synaptischen Aktivität beteiligt sein könnte. Im Gegensatz dazu behindert oligomeres Aβ die synaptische Aktivität. Daher ist ein immuntherapeutischer Ansatz, der Aβ zum Ziel hat, eine vielversprechende Behandlungsstrategie für AD. Eine der Herausforderungen eines immuntherapeutischen Ansatzes ist es spezifisch die toxischen, fehl-gefalteten Formen von Aβ zu bekämpfen ohne die physiologisch relevanten Aβ Monomere zu stören. Die Menge an natürlich vorkommenden Autoantikörpern gegen Aβ ist in AD Patienten erniedrigt. Im ersten Kapitel habe ich die Aß-Epitop-Region von natürlich vorkommenden Aβ-Autonatikörpern (Nabs-Aβ) mit Bindungsstudien ermittelt. Ich verglich die Bindung von Nabs-Aβ gegenüber einer Reihe von mutierten und verkürzten Aβ-Peptiden. Die Nabs–Aβ zeigten eine stärkere Bindung zum C-terminalen Ende von Aβ, das membrangebunden vorliegt. Das C-terminale Ende von Aβ ist entscheidend für die Oligomerisation. Deshalb könnten C-terminal-spezifische Nabs-Aβ helfen die Oligomerisierung zu minimieren. Zusätzlich könnte diese Spezifität eine Interaktion von nabs-Aβ mit membrangebundenen Amyloid-Vorläufer-Protein (APP), Aβ-Monomeren, und Aβ-Fibrillen ausschließen. Weitere Studien zur Epitop-Charakterisierung wurden mit ortsgerichteter Mutagenese durchgeführt. Die Ergebnisse zeigten dass Lysin an Position 28 und Isoleuzin an Position 32 von Aβ entscheidend für die Bindung von Nabs-Aß sind. Das Fehlen oder Ersetzen einer dieser beiden Aminosäuren führte zum Bindungsverlust. Zusätzliche Bindunsgstudien mit konformatorisch fixierten sogenannte Aβ-click-Peptiden zeigten dass nabs-Aβ spezifisch für niedermolekulare anti-parallele Aβ Dimere sind. Interessanterweise zeigten Nabs-Aβ eine exzellente Bindung mit Aβ mit 2 Muationen am C-terminalen Ende (Aβ1-40; G29,33 Ile). Die Charaktersisierung von Aβ1-40; G29,33 Ile zeigte, dass das Molekül einen unterschiedlichen Oligomerisierungsprozess durchläuft und SDS-stabile Trimere bildet. Zytotoxizitäts-Studien zeigten dass Aβ-Wildtyp unter bestimmten Inkubationsbedingungen toxische Oligomere bildet, während Aβ1-40; G29,33 Ile unter diesen Bedingungen nicht toxisch ist. Entsprechend meines derzeitigen Kenntnisstands ist Aβ1-40; G29,33 Ile die erste Aβ-Oligomer-Spezies die stabil ist und eine hohe Affinität zu Nabs-Aβ besitzt. Nicht-steroidale ani-inflammatorische Heilmittel haben Berichten zufolge einen positiven Behandlungs-Effekt bei AD. Ich untersuchte in dieser Arbeit die Rolle von CNI-1493, einer anti-inflammatorischen Verbindung. Die in vitro Experimente zeigten dass CNI-1493 Aß-Oligomere bindet und den Komplex in Richtung Monomere verschiebt. In dieser Arbeit habe ich im Detail die Effekte von zwei AD-Heilmittel-Kandidaten untersucht, die mit dem Immunsystem assoziiert sind; Nabs-Aβ und CNI-1493. Die Ergebnisse helfen unserem Verständnis über Nabs-Aβ und unterstützen ihre mögliche Rolle als sicheren und effektiven AD-Immuntherapie-Kandidaten. Der immunmodulatorische Wirkung von CNI-1493, sowie seine Effekte auf Aβ-Oligomerbildung machen dieses Molekül zu einem interessanten Arzeinmittel Kandidaten für AD Therapie-Studien. Zusätzlich könnte die neue Aβ-Mutante, nach weiterer Charakterisierung, als mögliche Vakzine oder diagnostisches Verfahren entwickelt werden.

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