Dokument: And now for something completely different: It’s Amyloid-β with two subunits
| Titel: | And now for something completely different: It’s Amyloid-β with two subunits | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=70988 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20251015-133034-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Schützmann, Marie P. [Autor] | |||||||
| Dateien: |
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| Beitragende: | Jun.-Prof. Dr. Hoyer, Wolfgang [Gutachter] Prof. Dr. Büll, Alexander K. [Gutachter] | |||||||
| Stichwörter: | Amyloid Aggregation; Amyloid Oligomers; Alzheimer's Disease | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Amyloid oligomers are soluble multimeric species of misfolded protein that in the case of Amyloid-β (Aβ) and α-synuclein (αsyn) are not only neurotoxic but hypothesized to be the culprit behind the devastating neurodegenerative diseases Alzheimer’s (Aβ) and Parkinson’s Disease (αsyn). However, due to the innate transience of oligomeric structures, investigating their effect on cellular processes and their interactions with other disease-relevant protein structures is complicated. In this thesis, we apply the synthetic Aβ dimer dimAβ to 1. investigate the source of Aβ oligomers in vivo, 2. their effects on neurons and 3. their potential to inhibit αsyn secondary nucleation.
1. DimAβ as well as Aβ42 are shown to oligomerize faster at acidic pH and become more stable in oligomeric form as well as cluster in superstructures. These conditions can be found in vivo in the endo-lysosomal system in which both dimAβ and Aβ accumulate. This compartment has also been shown to harbor an elevated concentration of Aβ, which reaches the same order of magnitude as the decreased critical oligomer concentration of Aβ42 at this pH. In combination with the known leakage of Abeta aggregates from lysosomes and the release of smaller oligomers from pH-upshifted oligomer clusters, the endo-lysosomal system is inferred to be a major source of neurotoxic Aβ oligomers. 2. DimAβ is evaluated as an Aβ oligomer model by showing its effect on neurons, including tau missorting, a decrease of neuronal activity and dendritic spine binding. In this regard it shows the same effect known for Aβ, but is far more consistent and stronger than Aβ oligomers, likely due to its kinetic stabilization. 3. DimAβ oligomers are off-pathway oligomers that are known to not promote but inhibit Aβ aggregation. I show that they also inhibit αsyn aggregation in a concentration-dependent manner. This extends the model of off-pathway oligomer inhibition of amyloid aggregation to not rely on matching sequences but other shared properties, such as hydrophobicity. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Physikalische Biologie | |||||||
| Dokument erstellt am: | 15.10.2025 | |||||||
| Dateien geändert am: | 15.10.2025 | |||||||
| Promotionsantrag am: | 10.06.2025 | |||||||
| Datum der Promotion: | 29.09.2025 |
