From Development to Neurodegeneration: understanding the dynamics and functions of protective microglial states – United_States_of_Microglia

Microglia, the brain-resident macrophages, play key roles in brain circuits and their dysfunction has been involved in most brain pathologies, from neurodevelopment to neurodegeneration. Recent studies showed that microglia exist in distinct cellular and transcriptomic states, during development, ageing and in neurodegenerative diseases. In particular, Disease Associated Microglia (DAM) are protective in the context of neurodegenerative conditions such as Alzheimer’s Disease (AD). Remarkably, a state that shares common transcriptomic features with DAM, called Axon-Tract associated Microglia (ATM), is found in the postnatal white matter and regulates myelination via Igf1 production. We recently showed that DAM derive from embryonic microglia and that ATM are already present in the fetal brain, where they preserve structural integrity at cortical boundaries, in part by producing the glycoprotein Spp1/Osteopontin.

Collectively, these observations raise the intriguing questions of (1) how similar/divergent ATM and DAM states are in terms of programs and induction, (2) by which molecular pathways they preserve brain homeostasis in different contexts, (3) what are the kinetics and potential relationships between the two states. We will tackle these issues in mice through an ambitious research program that takes advantage of state-of-the-art experimental approaches including spatial transcriptomics, in vivo manipulations, live-imaging, genetic models to label and tag microglial states, and conditional mutants targeting the Igf1 and Spp1/Osteopontin pathways. This will enable us to perform longitudinal studies of microglial states, from physiological prenatal life up to disease and neurodegeneration, using an AD mouse model.

Achieving our goals will rely on the synergy between partners and provide a novel framework for understanding how microglial states relate to specific functions and molecular pathways, from physiological development to neurodegeneration.