Characterising the role of ADAM17 in neuronal development in the context of Alzheimers disease

Owing the growing elderly population, the incidence of neurodegenerative diseases of ageing is steadily increasing during the last decades. These diseases are often complex and multi-factorial with overlapping symptoms and pathophysiological markers. Alzheimer's disease is the most common form of dementia and is characterized by intracellular tau accumulations and extracellular amyloid plaques. Although some genes have been identified as causal in some patients, the majority of cases occur sporadic and disease onset remains unexplained. Recent research has linked a heterozygous, single nucleotide variant in ADAM17 (SNV rs142946965) to
the onset of a mendelian form of AD, but the mechanistic link between the mutation and AD is not yet understood. The recent development in induced pluripotent stem cells technology allow for examination of the effects of genetic variants in a personalized manner. In this study, a stable iPSC line was generated using a fluorescence based CRISPR/Cas gene editing approach. To investigate the effect of the ADAM17 SNV rs142946965 mutation on early neuronal development, the generated clones were used for induction of differentiation into basal forebrain cholinergic
neurons and midbrain dopaminergic neurons, respectively. Neuronal differentiation was followed up by deep phenotyping including single-cell transcriptomics and metabolomics at early developmental stages. Five genes were found to be differentially expressed at all timepoints during basal forebrain cholinergic neuron differentiation between mutant and control and could be linked to impairments
in neuronal development. Metabolomic analysis also revealed perturbance of AD-relevant pathways, indicating the importance of ADAM17 in neuronal development and disease development. Overall, this study employed state-of-the-art CRISPR/Cas9 gene editing and multi-omics technologies to investigate the impact of ADAM17 on early neuronal development.