Research team
Microglia-neuron communication in health and disease (NeuroTalk2Mi).
Abstract
Microglia are the resident immune cells of the brain, and contribute to a wide range of cellular processes in both homeostasis and disease. They play a major role in the pathogenesis of Alzheimer's disease (AD), the leading cause of dementia and a major cause of death in the elderly. Microglia closely interact with neurons and modulate their function with high regional specificity, making them potential culprits behind the neuronal damage in AD. However, exactly how microglia and neurons interact and communicate, and how these interactions change in disease is not known. I hypothesize that an early hallmark of AD is the changing interactions between microglia and neighboring cells such as neurons, which contributes to progress of the disease and ultimately results in synaptic and neuronal loss. I will test this in human microglia by using a unique human xenotransplantation model, whereby I transplant human PSC-derived microglial progenitors into the cortex of healthy and APP-NLGF mice; microglia will acquire a human transcriptional and morphological signature, in vivo. Using RABID-seq to trace microglia-centric interactions with single-cell resolution, combined with 10X Genomics, I will precisely map the interactions of distinct subsets of microglia and neurons, to determine homeostatic molecular networks and how cell-to-cell communication is altered in the early stages of AD. Ultimately, this will allow me to identify specific molecular pathways which can be manipulated to support a beneficial function in microglia, while blocking detrimental effects, to protect neurons and arrest disease. Given that microglia are involved in multiple neurodegenerative diseases, finally understanding how they interact with other cells of the CNS will be a valuable resource to the greater neuroscience community in development, ageing, and disease.Researcher(s)
- Promoter: Mancuso Renzo
- Fellow: Mohebiany Alma Nazlie
Research team(s)
Project type(s)
- Research Project
All-for-one and one-for-all: Microglia-centric networks with neurons and astrocytes.
Abstract
The key to explaining neurodegenerative disease may lie in our understanding of microglial interactions with other CNS cells, which I plan to unravel using a combined human xenotransplantation model and barcoded rabies virus approach. Microglia (MG) are the resident immune cells of the brain, constantly extending and retracting their processes to monitor the surrounding environment. However they are not mere responders to disease or damage. Involved in neurogenesis, regulation of neuronal activity, and synapse formation and pruning, MG play important roles in shaping the brain and its normal functioning. However, we still do not know the cellular and molecular pathways responsible for maintaining a homeostatic profile in microglia, and how these change in disease. Nor do we know how communication with other cell types helps to regulate the microglial response in the development of disease such as Alzheimer's (AD). AD is the most common form of dementia, making up 60% of all cases, and extensive studies to understand the etiology has revealed MG as key players in AD, which is characterized by multiple neuropathologies. Using a novel human MG xenotransplantation model from my host group and cutting-edge techniques to label cells that have directly interacted with MG, my project focuses on the interplay between hMG and other cells of the brain. I will identify molecular and transcriptional networks involved in MG-centric interactions and how these contribute to AD development.Researcher(s)
- Promoter: Mancuso Renzo
- Fellow: Mohebiany Alma Nazlie
Research team(s)
Project type(s)
- Research Project