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Abstract

To date, there are only limited pharmacological treatments to cure AUD and the success rate is very low. Therefore, new therapeutic routes are warranted. This thesis aims to contribute to this need by identifying molecular mechanisms that are altered in AUD, considering the patient aspect through the use of human post-mortem brain samples, and compare the findings to a frequently used animal model of alcohol dependence. By combining multiple cutting-edge techniques, this study provides high evidence for further follow-up studies, where it will be possible to validate the findings in pre-clinical approaches and predict the relevance for the patient more precisely than previous studies. In addition, biomarkers for AUD, that are defined by this study, contribute substantially to the diagnosis of AUD on a molecular basis. The meta-analysis of three brain regions (study 2) –prefrontal cortex (PFC), nucleus accumbens (NAc) and amygdala (AMY)– identified common signatures comparing rodent, monkey, and human post-mortem brain tissue. In the PFC, we found commonly enriched pathways for cancerogenesis, pro-inflammatory processes, and oxidative stress. The analysis of the NAc resulted in no differentially expressed genes (DEGs) in the rodent model and less than 10 DEGs in humans, suggesting that this brain region is not significantly vulnerable to long-term alcohol abuse with prolonged abstinence. Further evidence was also found in the bulk sequencing approach (Study 1), where both methylome- and transcriptome-wide data of prefrontal and striatal regions were conducted, and the ventral striatum (VS) showed a limited number of DEGs and no overlapping genes in the data integration of methylation and transcription data. However, on the level of differentially methylated positions and regions, the VS was one of most affected regions observed. When comparing the results of all three brain regions in humans, SERPINA3 appears to be up-regulated independently of the region, suggesting this gene as a new biomarker for AUD. First preliminary snRNA-Seq data from the dorsomedial striatum of PD rats (Study 3) – the brain region that was also found in the human post-mortem brain to be most significantly altered on the multiomics level (Study 1) – suggests a pronounced relevance for oligodendrocytes and microglia in regard to altered transcripts that persist after long-term abstinence. These cell types have been previously found to be relevant in AUD patients and the post-dependent rats on several brain regions. III As indicated by studies 1-3, the immune system is strongly dysregulated in AUD. Therefore, in study 4, chronic alcohol consumption and alcohol dependence as potential risk factors for COVID-19 infection and severity was observed across multiple rat models of alcohol intake. Especially, the consistent up-regulation of ACE2 in lung tissue detected in all models as well as the reduction of Mas expression in the olfactory bulb led to the conclusion that alcohol intake – especially in a sub-chronic to chronic manner – might increase the propensity to develop a SARS-CoV2 infection and potentially, suffer from severe long-term consequences, such as anosmia.