Dokument: The role of the metalloprotease ADAMTS4 in Aβ peptide generation and Alzheimer’s disease
| Titel: | The role of the metalloprotease ADAMTS4 in Aβ peptide generation and Alzheimer’s disease | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=44252 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20171206-102525-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Walter, Susanne [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Weggen, Sascha [Gutachter] Prof. Dr. Schmitt, Lutz [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Alzheimer’s disease (AD) is the most common neurodegenerative disorder responsible for 60 - 80% of all dementia cases. The disease process starts with the accumulation of amyloid-β (Aβ) peptides in the brain, which form neurotoxic protein aggregates and trigger synaptic and neuronal loss. Aβ peptides (e.g., Aβ1-40 and Aβ1-42) are generated through sequential cleavage of the amyloid precursor protein (APP) by the proteases β- and γ-secretase. However, earlier studies had shown that the majority of insoluble Aβ peptides are truncated at the N-terminus with Aβ4-x peptides as the most abundant species. These N-truncated Aβ peptides could have an important role in the pathogenesis of AD, but their origins are unknown. We found that the Aβ peptide sequence contains putative cleavage sites for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4), and the central objective of this thesis was to determine the effects of ADAMTS4 on APP processing and Aβ generation in vitro and in vivo. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4-40 but unchanged Aβ1-x peptide levels as measured by mass spectrometry and ELISA. Co-immunoprecipitation studies provided evidence that APP and ADAMTS4 might interact in the early secretory pathway, and ADAMTS4 overexpression reduced mature APP levels and secretion of the soluble APP ectodomain APPs. Aβ4-x production was not dependent on prior cleavage of APP by β-secretase, and purified ADAMTS4 was able to convert Aβ1-40 into Aβ4-40, indicating that Aβ4-x peptides might be generated both within the cell and in the extracellular space. For in vivo analysis, ADAMTS4-/- knockout mice were crossed to the 5xFAD model of AD. Aβ4-40 levels were reduced by 50% and APPs levels were increased by 30% in the brains of 12-month-old 5xFAD / ADAMTS4-/- mice, confirming core findings of the in vitro studies. Surprisingly, in the adult murine brain ADAMTS4 was exclusively expressed in cells of the oligodendrocyte lineage. Cultured oligodendrocytes secreted a variety of Aβ species but Aβ4-40 peptides were absent in oligodendrocytes prepared from ADAMTS4-/- knockout mice, proving that ADAMTS4 is essential for Aβ4-x generation in this cell type. Finally, white matter structures in 5xFAD mice showed punctate deposits of Aβ4-x peptides, which were reduced in 5xFAD / ADAMTS4-/- mice. Taken together, the studies conducted in this thesis project established that N-truncated Aβ4-x peptides can be generated by the metalloprotease ADAMTS4. Importantly, they implicate oligodendrocytes as a novel pro-amyloidogenic effector in the pathogenesis of AD. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Neuropathologie | |||||||
| Dokument erstellt am: | 06.12.2017 | |||||||
| Dateien geändert am: | 06.12.2017 | |||||||
| Promotionsantrag am: | 15.09.2017 | |||||||
| Datum der Promotion: | 24.11.2017 |
