Prevention and treatment: Effects on pathological alterations in transgenic Alzheimer’s disease mouse models
by Martina Stazi
Date of Examination:2021-05-19
Date of issue:2021-06-21
Advisor:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Thomas Dresbach
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EnglishAlzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia worldwide. To date, no successful therapeutic approach to treat AD has been developed, hence preventive strategies started to become a major research focus. In this work, the effects of pharmacological treatment strategies such as chronic memantine, caffeine or riluzole supplementation, as well as the effect of a stimulating environmental living condition on the pathological alterations have been examined in Tg4-42hom and 5xFAD mice, representing two different AD mouse models. The Tg4-42 model overexpresses only the Aβ4-42 peptide mainly in the hippocampus, lacking any mutations linked to the familial form of the disease. Although this mouse model does not present overt extracellular Aβ plaques, Aβ4-42 forms neurotoxic aggregates that well correlate with the age- and dose-dependent pyramidal neuron loss in the CA1 region of the hippocampus as well as with robust learning and memory deficits. It could be shown that long-term oral treatment with either memantine, caffeine or riluzole completely rescued behavioural deficits in 6-month-old Tg4-42hom mice. Interestingly, these beneficial effects on learning and memory were accompanied by a significant amelioration of neuronal loss and a robust increase in neurogenesis. The present study presents evidence that long-term oral treatment with these drugs prevents behavioural decline as well as neuron loss and impaired neurogenesis in a mouse model reflecting the sporadic form of AD. Recently, epidemiological data revealed a potential protective role of physical exercise and cognitive stimulation on AD risk. Hence, it could be demonstrated in Tg4-42hom mice that living in a stimulating environment not only improves general behaviour but also ameliorates sensory-motor deficits. We have shown that the housing condition exerts a strong beneficial effect on a typical floating phenotype in Tg4-42hom mice, since none of the animals housed in an enriched environment presented that characteristic.The 5xFAD model is a well-characterized and commonly studied AD mouse model, reflecting first and foremost the familial form of the disease. In the present work, it could be demonstrated that, despite of an amelioration of memory deficits, chronic caffeine intake has no major influence on the typical pathophysiological alterations in the 5xFAD model, since neither changes with regard to Aβ plaque deposition, neuroinflammation, Aβ1-42 levels or APP processing were observed. These results suggest that a therapeutic intervention, such as chronic caffeine administration, might have a crucial impact on cognition without influencing the aggressive AD pathology observed in 5xFAD mice after onset of pathology.
Keywords: Behaviour; Learning and memory; Alzheimer’s disease; Neuron loss; Transgenic mice; Tg4-42; 5xFAD; Treatment