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Harnessing neuromodulation to target microglial activity in neurodegenerative diseases
Venkata Chaitanya Chirumamilla1, Muthuraman Muthuraman2
1The Zickler Family Prenatal Pediatrics Institute, Children's National Hospital, Washington, DC, United States.
Abstract:
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.
Insights
Neuromodulation may offer a novel therapeutic strategy for neurodegenerative diseases by targeting microglia, the brain's immune cells. This approach aims to restore neuroimmune homeostasis and improve brain health.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neurodegenerative diseases involve disrupted neuroimmune homeostasis, with microglia playing a key role.
- Microglia are involved in synaptic remodeling and neural circuit regulation, with functions varying by brain region and disease stage.
- Neuromodulation influences neural activity and downstream immune signaling in the central nervous system.
Purpose of the Study:
- To present a mechanistic framework for using neuromodulation to modulate microglial activity in neurodegenerative diseases.
- To integrate understanding of microglial heterogeneity, neuromodulation, and biomarkers for therapeutic targeting.
- To position microglia as measurable and biologically grounded therapeutic targets.
Main Methods:
- Synthesizing experimental findings from animal models and translational human studies.
- Examining activity-dependent neuron-microglia interactions.
- Analyzing modulation of inflammatory signaling pathways.
Main Results:
- Neuromodulatory interventions can influence microglial state, morphology, and function.
- Evidence suggests neuron-microglia interactions are key to neuromodulation's effects on microglia.
- The framework integrates microglial heterogeneity and neuromodulation mechanisms.
Conclusions:
- Neuromodulation presents a promising strategy for targeting microglial activity in neurodegenerative diseases.
- This approach offers a pathway to restore neuroimmune balance and potentially treat neurodegeneration.
- Further research integrating biomarkers and addressing translational challenges is needed.
