Project description
Microglial cells-neuron interactions in Alzheimer’s disease
Microglia are the immune cells of the brain, but they also play important roles in normal brain function; for example, they closely interact with neurons to influence neuronal differentiation and function. Microglia dysfunction is thought to contribute to psychiatric and neurological diseases, including Alzheimer’s disease (AD). The mechanisms microglia use to interact with neurons and how these change in AD is poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the NeuroTalk2Mi project aims to investigate this by transplanting human pluripotent stem cell-derived microglial progenitors into the cortex of healthy and AD mice, and tracing their interactions with neurons. The aim is to better understand how microglia-neuron interactions change with age, and how this might influence the development of AD.
Objective
Microglia are the resident immune cells of the brain, display extensive heterogeneity, 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 mortality worldwide. 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 pluripotent stem cell-derived microglial progenitors into the cortex of healthy and AD mice. Using RABID-seq combined with 10X Genomics to barcode microglia and subsequently trace their interactions with single-cell resolution, 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 molecules and molecular pathways which can be manipulated to support a beneficial function in microglia, while blocking detrimental effects, to protect neurons and prevent, slow, or ameliorate the disease. Given that microglia are involved in normal brain development and multiple neurodegenerative diseases, finally dissecting how they interact with other cells of the CNS will be a valuable resource to the greater neuroscience community with implications for development, ageing, and disease.
Fields of science (EuroSciVoc)
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Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
9052 ZWIJNAARDE - GENT
Belgium