From gene to function: Unraveling the molecular mechanisms of Alzheimer-associated ABCA7 risk variants in microglia biology using patient-derived iPSCs and chimeric mice models.

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-β 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 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 models 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.

Keywords:MICROGLIA, NEUROINFLAMMATION, ALZHEIMER'S DISEASE, GENETICS

Disciplines:Innate immunity, Neurological and neuromuscular diseases