Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental... Show moreAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental obstacles remain into understanding disease causation and nominating drug targets for a cure. With this work, we widen our understanding of ALS through the analysis of single-nuclei RNA-sequencing dataset of patients’ and control motorcortices. We show intrinsically higher expression of ALS-related genes in Extratelencephalic Neurons accompanied by selective vulnerability of subsets of cortical motor neurons. These changes are found with alterations in oligodendrocytes and microglia that widen our knowledge of cell-to-cell interactions in ALS. We use hiPSC-derived in vitro systems to model the molecular changes identified. Secondly, we offer a wide view on models of human brain cells in a dish to encompass protocols useful for modelling complex cell-to-cell interactions in ALS. Moreover, we describe a human in vitro system for the study of motor neuron that is highly reproducible, scalable and high-throughput. This new method allows the assessment of multiple cell lines in the same dish and could provide insights into heterogeneity in human populations and mechanisms disrupted in disease. We then use these models to further dissect molecular mechanisms disrupted in ALS. We undertake a discussion onto the future of the field and hopefully the opening to a more holistic approach to the understanding of ALS, where multidisciplinary techniques and the use of different models might expand our perspectives on the disease. Show less
How to define the preclinical Alzheimer's Disease state in otherwise healthy elderly. How to best select otherwise healthy elderly for clinical trials participation with a disease modifiying... Show moreHow to define the preclinical Alzheimer's Disease state in otherwise healthy elderly. How to best select otherwise healthy elderly for clinical trials participation with a disease modifiying compound. Difference between healthy elderly and subjects in the preclinical AD stage on biomarker level. Difference in cognitive performance in healthy subjects compared to neurodegenerative disease profiles. Show less
This thesis aimed to gain more insight into the role of iron in neurodegenerative diseases using high-field MRI. I investigated the pathological correlates of susceptibility-based contrasts on MRI,... Show moreThis thesis aimed to gain more insight into the role of iron in neurodegenerative diseases using high-field MRI. I investigated the pathological correlates of susceptibility-based contrasts on MRI, and how iron accumulation is associated with disease progression both ex vivo and in vivo. Show less
This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several... Show more This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease. Show less
