Microglia-centered cellular crosstalk in neurodegeneration

Neuroinflammation shaped by aberrant cellular interactions represents a hallmark of neurodegenerative diseases of the central nervous system (CNS). Microglia are specialized tissue-resident macrophages that reside in the CNS parenchyma and have emerged as central regulators of this aberrant cellular crosstalk. They integrate local signals and orchestrate the cellular interaction networks that underlie disease progression. Recent advances in single-cell and single-nucleus omics, in combination with spatially resolved approaches, have substantially advanced our understanding of microglial dynamics in neurodegeneration. These technological and conceptual advances have revealed an unexpected diversity of disease-associated microglial states and highlighted microglia as central organizers of multicellular interaction networks within diseased CNS tissue. In this chapter, we discuss how these advances have reshaped our understanding of microglia-centered cellular crosstalk in neurodegeneration. We focus on the diversification of neurodegenerative CNS microglial states, the interaction of microglia with neurons, glial cells, adaptive immune cells, and the vasculature. We further discuss how this framework provides a basis for therapeutic strategies aimed at modulating, replacing, or reprogramming microglia in neurodegenerative disease.