Exercise-modulated glial plasticity: unveiling mechanisms of neuroprotection in neurodegenerative disorders

Neurodegenerative diseases, including Alzheimer’s and Parkinson’s, are characterized by synaptic dysfunction, neuroinflammation, and impaired clearance of toxic aggregates such as amyloid-β (Aβ) and α-synuclein. Microglia and astrocytes, the brain’s primary immune and supportive glial cells, exhibit remarkable plasticity, adopting diverse reactive phenotypes in response to environmental cues. These reactive glial states range from those associated with pro-inflammatory or neurotoxic functions to those supporting
Recent evidence highlights exercise as a potent modulator of glial reactivity and plasticity. However, the precise molecular mechanisms underlying exercise-induced changes in glial function remain incompletely understood. For example, high-intensity interval training (HIIT) enhances astrocytic aquaporin-4 (AQP4) polarization, promoting Aβ clearance via the glymphatic system, while moderate exercise reduces microglial inflammatory responses in rodent models. Collectively, these findings underscore exercise’s potential to influence glial phenotypes and functions in ways that may support brain health, yet the detailed pathways and downstream effects remain to be elucidated.

Despite encouraging preclinical data, the translation of exercise-based interventions into clinical neurodegenerative disease management is limited by an incomplete understanding of exercise-modulated glial mechanisms. This Research Topic aims to address two critical questions:
1) How does exercise, through epigenetic or metabolic pathways, modulate the molecular signature and function of microglia and astrocytes to promote neuroprotection?
2) Can exercise-induced glial plasticity be harnessed to restore synaptic pruning, reduce neuroinflammation, promote the clearance of pathological proteins, and ultimately ameliorate neurodegenerative disease progression?

We welcome manuscripts that include—but are not limited to—the following themes:

1) Molecular determinants of exercise-modulated glial reactivity (e.g., AQP4 redistribution, Trem2 signaling).
2) Exercise-mediated regulation of synaptic pruning by microglia (e.g., complement pathways, CX3CL1-CX3CR1 axis).
3) Astrocyte–lipid metabolic interactions in exercise-induced glial reprogramming (e.g., adiponectin signaling, lactate shuttle).
4) Sex- or age-dependent variations in exercise-driven glial responses.
5) Clinical or longitudinal studies linking exercise modalities to glial biomarkers.
6) Novel mechanisms and functional outcomes of exercise-induced glial plasticity beyond the above themes.

Authors are encouraged to carefully describe glial phenotypes using specific molecular, cellular, and functional characteristics, in accordance with recent consensus guidelines.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Exercise, Microglial polarization, Astrocyte phenotype switching, Synaptic pruning, Amyloid-beta clearance, Neurodegenerative diseases

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.