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Selected Publication:
Hinteregger, B.
Integration of Metabolomics and already established Approaches for Characterization of an Alzheimer´s Disease Model.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 128
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- Authors Med Uni Graz:
- Advisor:
- Birner-Grünberger Ruth
- Khalil Michael
- Madl Tobias
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- Abstract:
- Many different transgenic mouse models have been established in recent years to study Alzheimer´s disease. Although none of these transgenic mouse models fully replicates the human disease, the ability to study similar pathological processes in living animals has provided new insights into the pathogenesis of the disease. Thus, the first aim of this thesis was to perform a comprehensive characterization of the novel Tg4-42 mouse model by integrating metabolomic phenotyping and already established approaches such as behavioral tests, histology and biochemistry for in-depth characterization and to better understand the underlying disease mechanisms. To reach this first aim, different behavioral tests, immunhistochemistry, biochemical analyses as well as untargeted NMR-based metabolic phenotyping of wild type and Tg4-42 +/+ mice of different ages were performed. Tg4-42 +/+ mice showed impaired learning behavior and memory deficits in the Morris water maze test. Furthermore, untargeted NMR-based metabolic profiling showed significantly decreased glutamine and 4-aminobutyrate levels in different brain areas compared to control mice. To verify these results, enzymes within this pathway were analyzed histologically resulting in significantly increased glutaminase as well as GAD67 levels in Tg4-42 +/+ mice. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation, loss of neurons as well as a knockdown of the retinoic acid receptor beta in Tg4-42 +/+ transgenic mice, the latter questioning the cause of the evaluated phenotype of these mice to be solely dependent on Aß4-42 expression. This was the reason, why for the second part of this thesis a different AD animal model, the APPSL, had been used. The described pathological processes and alternations in AD brains are thought to cause oxidative imbalance suggesting that oxidative stress plays a major role in AD progression. All these pathological events lead to the generation of toxic aldehydes, resulting in an accumulation of such highly reactive intermediates in the brain and blood. Therefore, a mechanism for rapid clearance of these highly diffusible and harmful aldehydes is crucial to protect cells and tissues from damage. In particular, the detoxification by enzymes such as aldehyde dehydrogenase 2 (ALDH2) plays a key role in oxidizing endogenous aldehydic products. For that reason, a variety of small molecule modulators of ALDH2 has been discovered which are able to enhance the catalytic activity of ALDH2 leading to an increased detoxification in cells. Thus, activation of the ALDH2 pathway could be a molecular target for AD. Therefore, the second aim of this thesis was to evaluate the effects of an ALDH2 agonist on AD disease progression in APPSL mice. To reach this aim male transgenic APPSL mice and their non-transgenic littermates received either an ALDH2 activator or vehicle via the drinking water for the duration of 2 or 4 months. Behavioral tests, immunohistochemistry as well as untargeted NMR-based metabolic phenotyping of all mice were performed. In vivo results revealed a highly significant improvement in spatial learning in APPSL+AD-9308 compared to APPSL animals. Moreover, untargeted metabolic phenotyping showed increased serum acetate levels in AD-9308 treated APPSL mice. Additionally, further measurements were performed to analyze treatment effects of the ALDH2 activator in APPSL mice which revealed decreased Aβ-40 and MDA levels due to the treatment. However, based on current results it is not yet possible to specify which pathways are influenced by the ALDH2 activator and further analyses are necessary to better understand the effects of this drug. Nevertheless, the results of this study demonstrate that increasing the detoxification activity of ALDH2 seems to be a promising approach to target Alzheimer´s disease pathology.