Dokument: A Molecular View on Alzheimer's Disease by Cryo Electron Microscopy
| Titel: | A Molecular View on Alzheimer's Disease by Cryo Electron Microscopy | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65404 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240408-123200-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Zielinski, Mara [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Schröder, Gunnar [Gutachter] Prof. Dr. Sachse, Carsten [Gutachter] Prof. Dr. Stahlberg, Henning [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 530 Physik | |||||||
| Beschreibung: | According to the World Health Organization, 55 million people worldwide live with dementia in 2023. This number is expected to rise to over 130 million cases by 2050. The most common form of dementia is Alzheimer’s disease, which accounts for 60-70% of all dementia cases. A hallmark of Alzheimer’s disease is the aggregation of amyloid-β into insoluble fibrils and their subsequent accumulation into extracellular plaques. However, the polymorphic nature of amyloid-β fibrils has long posed a challenge to structural studies. But recent advances in the field of cryogenic electron microscopy have led to tremendous progress in the structural elucidation of amyloid fibrils and amyloid-β fibrils in particular. The aim of this study is to gain further molecular insights on amyloid-β fibrils that play an important role in Alzheimer’s disease. Further, it provides an outlook on how structural investigations could contribute to the development of novel therapeutics and imaging tracers.
In this thesis, Alzheimer’s disease is investigated at the molecular level within the framework of the following four projects. (1) A common tool for studying Alzheimer’s disease are animal models, particularly transgenic mice. In this study, the structures of nine amyloid-β fibrils extracted from brain tissue of six transgenic mice were determined. Five of the determined fibril structures observed in three different mice present novel amyloid-β fibril folds. Furthermore, amyloid-β fibrils similar to those found in humans, mostly in familial cases of Alzheimer’s disease, were observed in three mice. Finally, one mouse showed amyloid-β fibrils similar to human amyloid-β fibrils, that are mostly observed in sporadic Alzheimer’s disease cases. (2) The study of in vitro amyloid-β fibrils under different fibrillisation conditions is key to finding a suitable laboratory model system for Alzheimer’s disease. In this chapter, the in vitro fibril structures of synthetic amyloid-β42 fibrillised at neutral pH are presented. Of the nine polymorphs observed in the data set, a reconstruction was possible for six polymorphs. The medium-resolution maps did not allow for de novo atomic model, but a schematic Cα-backbone trace could be generated for all polymorphs, allowing comparison with other published amyloid-β fibril structures. (3) Mutations in the amyloid precursor protein gene can cause early-onset familial Alzheimer’s disease. This is also the case for the Uppsala mutation, a multi-codon deletion that results in the deletion of six amino acids within the amyloid-β sequence. In this work, first the structure of in vitro amyloid-βUpp(1-42)Δ19-24 fibrils was determined. Afterwards, the structure of murine amyloid-βUpp(1-42)Δ19-24 fibrils, which is different from both determined in vitro polymorphs, is presented. Finally, cryogenic electron microscopy data of amyloid-βUpp(1-42)Δ19-24 fibrils purified from human brain tissue has been collected. Helical reconstruction yielded a high-resolution map for Tau paired helical filaments as well as medium resolution maps of Tau straight filaments and likely wild-type amyloid-β fibrils. (4) The Icelandic mutation in the amyloid precursor protein gene is the only intra-amyloid-β APP mutation that is not associated with a familial form of Alzheimer’s disease, but is protective against amyloid pathology and Alzheimer’s disease. In this study, we first investigated whether A2T amyloid-β42 can form fibrils in vitro. Subsequently, A2T amyloid-β fibrils were studied by cryogenic electron microscopy and the structures of the two most abundant polymorphs were solved to high resolution. Interestingly, one polymorph is identical to a cryogenic electron microscopy structure of in vitro wild-type amyloid-β42 fibrils. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Physik | |||||||
| Dokument erstellt am: | 08.04.2024 | |||||||
| Dateien geändert am: | 08.04.2024 | |||||||
| Promotionsantrag am: | 16.08.2023 | |||||||
| Datum der Promotion: | 05.02.2024 |
