The dual role of microglia in neurodegenerative diseases: A review

Microglial activation has increasingly been recognized as a central hub in the pathogenesis of neurodegenerative diseases, where it exerts dynamic regulatory roles characterized by a contest between neuroprotective and neurotoxic actions. However, the precise process underlying this interplay between the two opposing effects remains incompletely elucidated.

Moderate activation of microglia prevents the accumulation of neurotoxic substances, such as cellular debris and misfolded proteins, promotes neuronal survival by secreting neurotrophic factors, and induces self-limiting inflammation that exerts neuroprotective and repair-promoting effects. In contrast, chronic and persistent microglial activation driven by sustained elevations of pro-inflammatory cytokines, cGAS-STING-mediated DNA sensing, hyperactivation of membrane receptors (e.g., TREM2 and CX3CR1), mitochondrial dysfunction, accumulation of disease-associated proteins, and the emergence of regulatory lectins like Galectin-3, accelerates the progression of neurodegenerative diseases. Through multi-targeted and multi-mechanistic interventions aimed at enhancing microglial phagocytic activity, inhibiting aberrant complement-mediated synaptic pruning (C1q/C3/CR3), reducing neuroinflammation, modulating immune checkpoints (e.g., CD33 and TIM-3)-it is possible to preserve microglial clearance of pathological factors and support neuronal repair. These precision strategies prevent the erroneous engulfment of healthy synapses and promote M2-like polarization，thereby optimizing neuroprotective effects, and delaying or ameliorating the progression of neurodegenerative diseases.

This review outlines the dynamic "double-edged sword" role of microglia in neurodegenerative diseases and systematically summarizes the clinical and multi-targeted intervention strategies designed to precisely modulate their functions and skew them toward a neuroprotective phenotype.