From gene to function: Unraveling the molecular mechanisms of Alzheimer-associated ABCA7 risk variants in microglia biology. 01/11/2022 - 31/10/2026

Abstract

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.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

From gene to function: Unraveling the molecular mechanisms of Alzheimer-associated ABCA7 risk variants in microglia biology. 01/11/2021 - 31/10/2022

Abstract

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.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project