Systems level mapping of neuron-to-microglia signaling in the healthy and diseased brain

Neurons and microglia engage in a complex, symbiotic relationship that is pivotal for maintaining
healthy brain homeostasis and responding to neurodegenerative challenges. We aim to elucidate the
intricate bi-directional signaling between neurons and microglia, both during homeostasis and
neurodegeneration. We posit that neuronal signals are crucial for defining microglial identity and
function, and these signals likely undergo significant changes in neurodegenerative contexts,
potentially driving microglia towards disease-associated states (DAM). The complex role of DAM in
conditions like Alzheimer's underscores the need for a deeper understanding of these dynamics. We
will map the secretome of neurons in both healthy and diseased brains using in vivo proteinproximity labeling and combine this with bio-informatic analysis to predict key neuronal signaling
molecules and their receptors on microglia. This knowledge will guide an innovative in vivo CRISPR/
Cas9 screening in iPSC-derived microglia transplanted into mouse brains to determine molecular
drivers of microglial identity, activation, and transition towards DAM during Tau-induced
neurodegeneration. This will then be leveraged to develop targeted therapeutic strategies to
ameliorate microglial function in neurodegenerative disease. This project will offer a deeper
understanding into the bi-directional communication between neurons and microglia and may reveal
new approaches for treating neurodegenerative disorders