Dokument: Impact of platelet-mediated inflammation on Alzheimer's disease progression and the interaction between collagen receptor glycoprotein VI and amyloid-β 40
| Titel: | Impact of platelet-mediated inflammation on Alzheimer's disease progression and the interaction between collagen receptor glycoprotein VI and amyloid-β 40 | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=62951 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240801-093304-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Toska, Laura Mara [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Elvers, Margitta [Gutachter] Prof. Dr. Hidalgo, Patricia [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | With the aging population, neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a major health problem worldwide. AD is a multifactorial neurodegenerative disorder associated with the development of cognitive impairment due to neuronal cell loss. Neuropa-thologically, AD is characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofi-brillary tangles and neuroinflammation in the brain. In addition, Aβ can also accumulate in cere-bral blood vessels, which is referred to as cerebral amyloid angiopathy (CAA). CAA is associ-ated with the degeneration of the vessel wall, resulting in decreased cerebral blood flow and progressive cognitive impairment. Platelets are key players in the regulation of hemostasis and are involved in acute and chronic inflammatory processes through their interaction with inflam-matory and endothelial cells. In recent years, there has been increasing evidence for platelets to be involved in the progression of AD. In this context, short-term treatment of the transgenic APP23 mouse model of AD with the platelet antagonist clopidogrel resulted in a reduction of CAA burden.
The aim of the present study was to further investigate the role of platelets and, in particular, the role of the major platelet collagen receptor GPVI, in the progression of AD. In the present study, GPVI was identified as a direct binding partner of Aβ40 at the platelet surface. Binding of Aβ40 to GPVI triggered GPVI surface externalization, ATP release and platelet aggregation. In addition, GPVI is critically involved in platelet-mediated formation of amyloid-β aggregates in vitro. Thus, blocking or deletion of GPVI led to a significant reduction of Aβ aggregation in vitro. Moreover, platelet stimulation with Aβ40 has been shown to trigger, in part via GPVI re-ceptor, the release of fibrinogen that co-localized with amyloid-β aggregates in vitro. Further-more, the present study investigated the influence of Aβ40 on platelet-triggered inflammation and neutrophil recruitment. Stimulation of murine platelets with Aβ40 induced the formation of platelet-neutrophil aggregates. Subsequent in vitro analysis of human and murine neutrophils revealed increased platelet-mediated neutrophil adhesion after Aβ40 and ADP stimulation. However, the formation of neutrophil extracellular traps was not observed under these condi-tions. In contrast to platelets, murine neutrophils were not substantially involved in the for-mation of amyloid-β aggregates in vitro. Stimulation of platelets with Aβ40 triggered GPVI-dependent ROS production and, to some extent, GPVI-dependent TGF-β1 release. Moreover, this work describes for the first time an age-dependent migration of platelets into the brain parenchyma in WTmT/mG;PF4Cre+ and APP23mT/mG;PF4Cre+ mice, with an earlier onset in the hippocampus of APP23mT/mG;PF4Cre+ mice. In the brain of aged APP23-mT/mG;PF4Cre+, platelets were localized around amyloid plaques and in close contact to mi-croglia. Taken together, this work identified the GPVI receptor as binding partner for Aβ40 at the plate-let surface that contributes to the formation of amyloid-β aggregates by platelets in vitro. Moreover, the results of this work suggest that Aβ40 impact the platelet-mediated inflamma-tion. In addition, platelets were detected around amyloid plaques in the brain parenchyma of aged APP23mT/mG;PF4Cre+ mice. This work provides further knowledge about the role of platelets in AD and suggests that anti-thrombotic therapy might be beneficial of patients with AD. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 01.08.2024 | |||||||
| Dateien geändert am: | 01.08.2024 | |||||||
| Promotionsantrag am: | 07.02.2023 | |||||||
| Datum der Promotion: | 15.06.2023 |
