Dokument: Charakterisierung der Interaktion von β-Amyloid mit Membranen mittels Nanodisks als Modellmembransystem
| Titel: | Charakterisierung der Interaktion von β-Amyloid mit Membranen mittels Nanodisks als Modellmembransystem | |||||||
| Weiterer Titel: | Characterisation of Amyloid β Membrane Interaction using Nanodiscs as a Model Membrane System | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=39577 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20170905-094334-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Thomaier, Maren [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Willbold, Dieter [Gutachter] Prof. Dr. Jaeger, Karl-Erich [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | Alzheimer-Demenz ist eine neurodegenerative Krankheit und die häufigste Form der Demenz. Im Verlauf der Krankheit werden Nervenzellen im Gehirn irreversibel geschädigt, was zu Gedächtnisverlust und Wahrnehmungsstörungen führt. Die Aggregation des Amyloid-β (Aβ) Peptides von seiner monomeren nicht toxischen Form über toxische Oligomere hin zu amyloiden Fibrillen und Aggregaten spielt eine entscheidende Rolle in der Krankheit. Es ist jedoch noch nicht geklärt, welcher Mechanismus zum Polymerisationsprozess führt. Ebenfalls sind trotz intensiver Forschung, die zugrunde liegenden molekularen Mechanismen, welche zur Toxizität der Oligomere führen, noch ungeklärt. Für beide Mechanismen ist die Interaktion von Aβ mit neuronalen Zellen entscheidend, die jedoch noch nicht aufgeklärt ist.
In dieser Arbeit wurden erstmalig Nanodisks verwendet, um die Interaktion von Aβ mit Membranen zu untersuchen. Nanodisks bestehen aus zwei Kopien des Proteins MSP (membrane scaffold protein), die eine Lipiddoppelschicht umgeben. Sie sind exzellente Modelmembransysteme um Protein Membran Interaktionen zu analysieren. Hier konnte gezeigt werden, dass sie sich für die Untersuchung von Aβ mit Membranen eignen. Protokolle für die Assemblierung mit neuen Lipidmischungen aus Lipiden, die sich in Lipid-Rafts von neuronalen Zellmembranen befinden, wurden etabliert und die Stabilität der Nanodiscs wurde mittels analytischer Größenausschlusschromatographie untersucht. Um Information über die Bindung von Aβ an Membranen und die damit verbundenen strukturellen Änderungen zu gewinnen, welche wahrscheinlich zur Membraninsertion führen, sind hochaufgelöste Strukturen erforderlich. Dies war bisher nicht möglich, da die geeigneten Modelmembransysteme fehlten. In der vorliegenden Arbeit zeigten erste NMR spektroskopische Untersuchungen, dass Aβ an Gangliosid GM1 haltige Nanodisks bindet und mit weiteren Optimierungen könnten Nanodisks als hervorragende Model Membran Systeme für die Untersuchung von Aβ in Membranumgebung dienen. Um die molekularen Voraussetzungen der Aβ-Membran-Bindung zu untersuchen wurden verschiedene Nanodisks mit variierenden Lipiden, bezüglich der Ladung der Kopfgruppe wie auch der GM1 Konzentration, eingesetzt. Fluoreszenz Titrations Experimente wurden etabliert und eine hoch affine Bindung von DAC-Aβ(1-40) an GM1 Nanodiscs in GM1 Konzentrationsabhängigkeit wurde entdeckt und charakterisiert. BioLayer Interferometrie (BLI) Experimente bestätigten die Bindung von Aβ(1-40) an GM1 Nanodisks. Mittels BLI wurde zusätzlich die Bindung von Aβ(1-42) an Nanodisks untersucht. Es bindet ebenfalls mit hoher Affinität an GM1 enthaltende Nanodisks und auch im gleichen nanomolaren Bereich wie Aβ(1-40). Interessanterweise banden weder Aβ(1-40) Oligomere noch Aβ(1-42) Oligomere an GM1 enthaltende Nanodisks, was darauf hinweist, dass die GM1-Membran-bindenden Regionen in Aβ Monomeren in Aβ-Oligomeren verdeckt sind. Nanodisks sind somit geeignete Modelmembransysteme um die Bindung und Interaktion von Aβ an und mit Membranen zu analysieren und charakterisieren.Alzheimer’s disease is a progressive neurodegenerative disease and the most common form of dementia. During the progression of the disease, neuronal nerve tissue is irreversibly damaged causing loss of memory and cognitive decline. The aggregation of amyloid β (Aβ) peptide from its monomeric non-toxic form over toxic oligomeric species to amyloid fibrils and aggregates is thought to play an important role in the disease. However, it is still unclear which mechanism causes the polymerisation process. Moreover, despite extensive research, the underlying molecular mechanism by which oligomeric Aβ species exhibit toxicity is still enigmatic. For both mechanisms, Aβ interaction with neuronal cell membranes is crucial. However, Aβ interaction with membranes has not been completely elucidated yet. In this work, nanodiscs were firstly used to study the interactions of Aβ with membranes. Nanodiscs are composed of two copies of the membrane scaffold protein surrounding a lipid bilayer. They are excellent model membrane systems for studying protein-membrane interactions, e.g. they have been shown to allow straight forward use of biophysical methods e.g. surface plasmon resonance, BioLlayer Interferometry (BLI) or nuclear magnetic resonance (NMR) spectroscopy to membrane inserted proteins. In this work their suitability to investigate the membrane interaction of Aβ is shown. Protocols for the assembly of nanodiscs with new lipid mixtures found in lipid rafts of neuronal cell membranes were established and the stability of nanodiscs was assessed by analytical size exclusion chromatography. In order to gain further knowledge about the binding of Aβ to the membrane and connected structural secondary changes presumably leading to membrane insertion, high resolution structures are required. Yet, this has been hampered by the lack of an appropriate model membrane system. In this work, first NMR spectroscopy results revealed a binding of Aβ to GM1 containing nanodiscs. By further optimisation nanodiscs could serve as an excellent model membrane system to study Aβ in a membrane environment. To analyse the molecular requirements of Aβ membrane binding, different nanodiscs varying in their lipid composition, regarding the charge of the head group as well as ganglioside GM1 concentration, were tested for membrane interaction with Aβ. Therefore fluorescence titration experiments were established and a high affinity binding of DAC-Aβ(1-40) to GM1 containing nanodiscs in a GM1 concentration dependent manner was found. BLI experiments confirmed completely binding of Aβ(1-40) to ganglioside GM1 containing nanodiscs. BLI allowed to extend binding studies to Aβ(1-42), which also bound with high affinity to GM1 nanodiscs in the same nanomolar range than Aβ(1-40). Interestingly, neither oligomeric Aβ(1-40) nor oligomeric Aβ(1-42) did bind to GM1 containing nanodiscs, indicating GM1-membrane binding regions of the Aβ monomers are masked in the Aβ oligomers. Thus nanodiscs are suitable model membrane systems to analyse and characterise Aβ membrane binding and interaction revealing new insights. | |||||||
| Quelle: | Allen, J. A., R. A. Halverson-Tamboli, et al. (2007). "Lipid raft microdomains and neurotransmitter signalling." Nature Reviews Neuroscience 8(2): 128-140.
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| Rechtliche Vermerke: | Sperrvermerk | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | 06.2012-02.2016 | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 05.09.2017 | |||||||
| Dateien geändert am: | 05.09.2017 | |||||||
| Promotionsantrag am: | 13.01.2016 | |||||||
| Datum der Promotion: | 09.02.2016 |
