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From gene to function: Unraveling the molecular mechanisms of Alzheimer-associated ABCA7 risk variants in microglia biology.

Alzheimer's disease (AD) is a complex neurodegenerative disease and the most common form of dementia worldwide. The main pathological hallmark is the extensive accumulation of intracellular amyloid-? plaques and extracellular tau tangles, in which genetics play a fundamental role. Large-scale genetic studies place microglia dysfunction central to the etiology of AD, wherein genetic variants are classified in three major pathways: inflammation, lipid metabolism and endocytic trafficking. Yet, functional data validating the link between these variants, microglia pathways and AD pathology is still lacking. Thus, there is a critical need to understand the contribution of individual risk genes to microglia function. In this project, I aim to elucidate the role of the risk gene ATP-binding cassette transporter, subfamily A member 7 (ABCA7) in AD by uncovering the molecular mechanisms underlying two high-risk variants (odds ratio=2.8,4.5). Therefore, I will generate isogenic cell lines using patient iPSC-derived microglia and cutting-edge CRISPR technologies. I will use our novel humanized chimeric mice model and multi-OMICS approaches to reveal differences between diseased and healthy microglia. In addition, as ABCA7 is a major brain lipid distributor implicated in all three pathways, I will determine the impact of altered lipid homeostasis on said pathways. The outcome of this project will deliver invaluable insights concerning AD research and ultimately novel therapeutic targets.
Date:1 Nov 2021 →  31 Oct 2022
Disciplines:Single-cell data analysis, Genetics, Stem cell biology, Neurosciences not elsewhere classified