Die Auswirkungen von ∆9-Tetrahydrocannabinol auf Gedächtnisstörungen und die Aβ-Pathologie im 5xFAD-Mausmodell

by Jannek Moritz Wagner
Doctoral thesis
Date of Examination:2024-09-24
Date of issue:2024-09-13
Advisor:Dr. Yvonne Bouter
Referee:Dr. Yvonne Bouter
Referee:Prof. Dr. Thomas Dresbach
Persistent Address: http://dx.doi.org/10.53846/goediss-10730

 

 

Files in this item

Name:Wagner_Jannek Moritz_Dissertation_ABGABE_SUB.pdf
Size:8.48Mb
Format:PDF

This file will be freely accessible after 2025-09-23.

Abstract

English

Alzheimer´s disease (AD) is the leading cause for dementia worldwide. It is characterized by a progredient cognitive decline, memory deficits and deposits of proteins called Amyloid beta (Aβ). Familial AD is characterized by distinct mutations in the Aβ processing enzymes and the amyloid precursor protein (APP). The mouse model 5xFAD carries five of these mutations and Aβ cumulates quickly, accompanied by neuron loss and cognitive deficits. The endocannabinoid system is involved in modulating manifold cellular processes and it is already altered in early stages of AD. Cannabinoids have positive effects in different neurodegenerative diseases without major side effects, thus making it a promising therapeutic target for treating AD. In this work 5xFAD mice were treated with low doses of the phytocannabinoide ∆9-Tetrahydrocannabinol (THC) either prophylactic, before AD-symptoms occur, with a subsequent washout period or therapeutic in an early stage of the disease with cognitive deficits already present. The behavioural tests of this work showed no major side effects of the chosen THC-dosage. The Open-Field-Test indicated wildtype-like activity levels after the preventative treatment and wildtype-like anxiety levels of the therapeutic treated 5xFAD mice, but these results could not be proven in other behavioural tests. In the Morris-Water-Maze-Test and the Novel-Object-Recognition-Test cognition was restored in both treatment groups. The working memory was not affected by THC. The pan-Aβ-plaqueload was significantly reduced in both groups. Which could be confirmed in an amyloid PET scan. The prophylactic treated group showed long lasting effects of THC with intact cognitive abilities of these mice even three months after the treatment has been completed. Thus, THC is able to delay the accumulation of Aβ and the onset of AD symptoms. Furthermore, the therapeutic treatment group had reduced levels of higher aggregated Aβ, but without additional improvements of cognitive abilities, suggesting that lesser aggregated Aβ is responsible for cognitive deficits. This work shows that THC is able to prevent and reverse cognitive deficits in 5xFAD mice, accompanied by a significant reduction in the pan-Aβ-plaqueload.
Keywords: Alzheimer´s; Alzheimer's disease; Dementia; AD; A-beta; Cannabinoids; THC; 5xFAD; behavior; PET; Morris Water Maze; amyloid