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: 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, Amyloid oligomer-specific autoantibodies, Oligomere, Antikörper, Morbus Alzheimer, AD immunotherapy, Naturally occurring autoantibodies, Amyloid beta, 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.

Zusammenfassung:
The broad objective of this study is to unravel the potential effect of naturally occurring autoantibodies (NAbs) and CNI-1493 (immunomodulatory compound) on Amyloid beta peptide (Aβ) oligomers. Extracellular accumulation of Aβ peptide in the brain is suspected to cause and trigger the progression of Alzheimer’s disease (AD). The exact physiological role of Aβ remains unclear. The oligomeric forms Aβ impair synaptic activity. Hence, immunotherapeutic approach targeting Aβ is one of the promising strategies to treat AD. One of the challenges in the immunotherapy approach is to specifically target the toxic misfolded forms of Aβ without disturbing the physiological levels of Aβ monomers. Naturally occurring autoantibodies against Aβ are reduced in AD patients. In the first chapter, I have characterized the Aβ epitope region of Aβ specific-naturally occurring autoantibodies (NAbs-Aβ) using binding studies. I compared the binding ability of NAbs-Aβ towards a variety of mutated and truncated Aβ peptides. NAbs-Aβ had greater binding ability towards the C-terminal sequence of Aβ, which is membrane bound. The C-terminal end of Aβ is crucial for the formation of Aβ oligomerization. Hence, C-terminal specificity of NAbs-Aβ could help in the minimizing of Aβ oligomerization. Additionally, this specificity also rules out the possible interactions of NAbs-Aβ with membrane bound amyloid precursor protein (APP), Aβ monomers and fibrils. Further studies on Aβ epitope characterization of NAbs-Aβ were performed using site-directed mutagenesis. The results indicated that the lysine at 28th and isoleucine at 32nd position of Aβ are crucial for the binding of NAbs-Aβ. Deletion or substitution of any of these two amino acids at their respective positions lead to loss of binding. Additional binding studies using conformationally fixed ‘click’ Aβ peptides indicated that the NAbs-Aβ are specific for low-molecular weight anti-parallel dimers. Interestingly, NAbs-Aβ showed excellent binding towards Aβ with two substitution mutations at C-terminal (Aβ1-40;G29,33Ile) end. In the second chapter, characterization of Aβ1-40;G29,33Ile showed that the peptide undergo a different oligomerization process to form SDS-stable trimers. Cytotoxicity studies showed that Aβ wild type forms toxic oligomers at certain incubation conditions where as Aβ1-40;G29,33Ile remains non-toxic under the same conditions. In-line with the results, according to my current understanding, Aβ1-40;G29,33Ile is the first oligomeric Aβ species that is stable and has high affinity to NAbs-Aβ. Non-steroidal anti-inflammatory drugs are reported to provide beneficial effects in AD. In the third chapter, I have investigated the role of CNI-1493, which is an anti-inflammatory drug. In vitro studies show that CNI-1493 binds to Aβ oligomers and destabilizes the complex to monomers. In this study, I have characterized in detail, the effect of two immune system related AD drug candidates, NAbs-Aβ and CNI-1493, on Aβ oligomers. These findings help our understanding about the NAbs-Aβ and support their potential role as a safe and efficient AD immunotherapy candidates. The immunomodulatory effect combined with its role on Aβ oligomers make CNI-1493 an interesting drug candidate for AD therapeutic studies. In addition, the novel Aβ oligomer could be developed as a potential vaccine and diagnostic tool for NAbs-Aβ after further characterization.

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