The dual role of microglia in neurodegenerative diseases: A review

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.