Effects of a THC-based Alzheimer Therapy on theNeuron Loss, Neurogenesis, and Inflammation
Başlık çevirisi mevcut değil.
- Tez No: 723839
- Danışmanlar: DR. YVONNE BOUTER
- Tez Türü: Yüksek Lisans
- Konular: Tıbbi Biyoloji, Medical Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2018
- Dil: İngilizce
- Üniversite: Georg-August-Universität Göttingen
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 64
Özet
Dadurch, dass die Menschen weltweit eine steigende Lebenserwartung haben, wird es zu einer ansteigenden Prävalenz der Alzheimer-Erkrankung kommen. Aktuell zugelassene Medikamente werden eingesetzt, um das Fortschreiten der kognitiven Dysfunktion und Verhaltensdefizite positiv zu beeinflussen. Derzeit existieren keine zugelassenen Behandlungsansätze, um dieses Fortschreiten aufzuhalten oder die Erkrankung zu heilen. Seit einiger Zeit steigt das Interesse am Endocannabinoidsystem (ECS) in Forschung und medizinischem Einsatz von Inhaltsstoffen der Cannabispflanzen als potenzieller Behandlungsansatz in der Alzheimer-Erkrankung. Sowohl In-Vivo-, als auch In-VitroStudien zeigen, dass Endocannabinoide in die Pathologie der Alzheimer-Erkrankung in Bezug zu Abeta- und Tau-Pathologie, Neuroinflammation, Zelltoxizität, mitochondrialer Dysfunktion und oxidativem Stress eingreifen können. In diesem Projekt wird der Einfluss von Tetrahydrocannabinol (THC) in einem Modell für die sporadische Alzheimer-Erkrankung (Tg4-42) in zwei Behandlungsansätzen untersucht. Dazu wurde der Nervenzellverlust und die Neurogenese, als auch die CannabinoidRezeptor-1-Expression (CB1) im Gyrus dentatus analysiert. THC als Inhaltsstoff der Cannabispflanze ist ein partieller Agonist der Cannabinoid-Rezeptoren und beeinflusst das ECS. Tg4-42-Mäuse exprimieren intraneuronal menschliches Abeta, weshalb sie einen signifikanten Nervenzellverlust in der CA1 Region des Hippocampus zeigen. Dieser wird sowohl immunhistochemisch, als auch in Verhaltensversuchen, wie dem Morris-WaterMaze sichtbar, wodurch diese Mauslinie als Modell für die sporadische AlzheimerErkrankung anerkannt ist. Das THC wurde den Mäusen über 6 Wochen täglich mit einer Konzentration von 20 mg/kg KG intraperitoneal verabreicht. In einem präventiven Behandlungsansatz beginnt die Behandlung mit 3 Monaten, in einem therapeutischen Behandlungsansatz mit 5 Monaten. Um den Einfluss von THC auf die CB1-Expression zu beurteilen, wurde die DABImmunhistochemie durchgeführt. Aktuelle Erkenntnisse zeigen eine Desensibilisierung der CB1-Rezeptoren, eine signifikante Verringerung der Mikrogliose und eine konstante Astrogliose im Gyrus dentatus der Tg4-42 durch die THC-Behandlung
Özet (Çeviri)
The rise in an aging population worldwide will cause an increase in the prevalence of Alzheimer's disease among older people. To date, approved treatments used to slow down the progression of cognitive symptoms and to reduce problematic behaviours in AD. However, no pharmaceutical approach has been shown to have a real clinical benefit to treat Alzheimer's disease progression. Recently, there has been spreading interest in the modulation of the endocannabinoid system (ECS) and the medical use of the bioactive components of cannabis plant as a potential therapeutic approach to treat Alzheimer's disease. Several in vitro and in vivo studies showed that targeting the endocannabinoid system with the usage of cannabinoids can be beneficial to alleviate key hallmarks of AD, including Aβ and tau aberrant processing, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. In this project, the effects of Tetrahydrocannabinol (THC) administration were investigated on the neuron loss, neurogenesis, expression of endocannabinoid receptor 1 and neuroinflammation in two different age groups of the Tg4- 42 mouse model. THC is an active constituent of cannabis and a partial agonist to endocannabinoid receptors appeared as a prominent candidate for the modulation of ECS. Tg4-42 mice develop severe hippocampal neuron loss and memory deficits correlating with intraneuronal Aβ expression with no plaque and neurofibrillary tangle formation. Thus, Tg4-42 is a valuable AD mouse model displaying key hallmarks of the sporadic AD. A preventative treatment group received the daily injection of THC for six weeks starting at the age of 3 months was compared to a therapeutic group receiving same treatment starting at the age of 5 months. For all steps, vehicle-treated control groups were maintained for both experimental groups. In this present work, it could be demonstrated that the number of immature neurons increased in the dentate gyrus of Tg4-42 mice in the therapeutic treatment group, whereas not in the preventative treatment group. Moreover, the stereological analysis revealed the significant increase in the number of neurons in the dentate gyrus upon THC administration in the therapeutic group. In order to assess the impact of THC treatment on the expression of cannabinoid receptor 1 and neuroinflammation markers in the therapeutic group, DAB immunohistochemistry was performed. The present findings provide evidence for desensitization or internalization of CB1 receptor, the significant decrease in microgliosis, and the constant level in astrogliosis in the dentate gyrus of Tg4-42 mice upon THC administration.
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