Harnessing neuromodulation to target microglial activity in neurodegenerative diseases.

Neurodegenerative diseases are increasingly understood as conditions of disrupted neuroimmune homeostasis in which microglia play an important, dynamic, and state-dependent role. Beyond their immune functions, microglia continuously monitor neuronal activity, participate in synaptic remodeling, and contribute to neural circuit regulation in ways that vary across brain regions, disease types, and stages of neurodegeneration. In parallel, neuromodulation can modify neural activity patterns, thereby influencing downstream cellular responses and immune-related signaling within the central nervous system. Accumulating experimental evidence suggests that neuromodulatory interventions can influence microglial state, morphology, and function through activity-dependent neuron-microglia interactions and modulation of inflammatory signaling pathways. By synthesizing findings from both experimental animal models and translational human studies, this chapter presents a mechanistic framework for examining how neuromodulation may be leveraged to modulate microglial activity in neurodegenerative diseases. This approach integrates current understanding of microglial heterogeneity, neuromodulation mechanisms, biomarker strategies, and key translational challenges, with the goal of positioning microglia as measurable and biologically grounded therapeutic targets.