Partners in crime? Deciphering microglia astrocyte communication in Alzheimer's disease.
Abstract
Alzheimer's disease is a complex neurodegenerative disease, pathologically defined by accumulation of extracellular amyloid-beta plaques, and intracellular neurofibrillary tau tangles, combined with neuronal loss, (astro)gliosis and inflammation. Although microglia are the hub of inflammatory events, they do not act alone. Activated microglia have been shown to induce the reactive astrocyte phenotype A1, thus pointing to a role for a coordinated multicellular response in the diseased brain. In this project, I will characterize microglia-astrocyte communication at the single cell level to map their molecular interactome and dissect specific changes that could contribute to AD. I will use an AD mouse models where I will: 1) investigate astrocytes transcriptional profiles in the presence of mouse and human microglia and after microglial ablation using PLX3397. 2) investigate physical cellular interaction with RABID-seq and through single-cell multi-omics, to finally bring to light physical interaction patterns of microglia and astrocyte phenotypes. 3) I will compile a large database of microglia-astrocyte interaction patterns that I will validate in human tissue. I will use this one-of-a-kind biological and computational framework to decipher cell-cell interactions and the molecular basis of cellular states, which will be a pivotal work to finally shed light on AD disease mechanism and provide new therapies.Researcher(s)
- Promoter: Mancuso Renzo
- Fellow: Bijnens Baukje
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 using patient-derived iPSCs and chimeric mice models.
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-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.Researcher(s)
- Promoter: Mancuso Renzo
- Fellow: Bijnens Baukje
Research team(s)
Project type(s)
- Research Project