Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged...

Maintaining homeostasis in the Central Nervous System (CNS) requires constant, bidirectional molecular interactions between microglia and astrocytes. This intercellular communication, mediated by cytokines, extracellular vesicles, purinergic signals, and connexin hemichannels, synchronizes immune surveillance, neurogenesis, and synaptic pruning under physiological conditions. However, this interaction can drive persistent neuroinflammation in chronic Neurodegenerative Disorders (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD).

Gene disease association analyses and review of existing literature were employed to identify shared glial regulators and molecular mediators across multiple neurodegenerative disorders, supported by schematic diagrams illustrating intercellular signaling dynamics Results: Deregulated astrocytes sustain microglial activation, creating self-amplifying inflammatory loops, while activated M1 microglia induce the conversion of astrocytes into neurotoxic A1 astrocytes via factors such as IL-1α, TNF-α, and complement C1q. Important mediators, such as prostaglandins, IL-1β, and IL-18, further contribute to demyelination, astrogliosis, and excitotoxicity. A convergent glial activation axis identifies shared regulators across several neurodegenerative disorders, including TREM2, GRN, LRRK2, and BDNF.

Active research targeting reactive astrogliosis and microglial reprogramming towards homeostatic phenotypes shows therapeutic promise. Nevertheless, CNS immune complexity, translational challenge, and inter-patient immunological variability underscore the need for individualized, combinatorial therapeutic strategies and human-relevant experimental models.

The microglia-astrocyte axis plays a dual role in neuro-immune homeostasis and neurodegeneration, representing critical therapeutic targets for NDDs and requiring further mechanistic and translational investigation.