Emerging roles of microglia and neuroinflammation in Huntington's disease: From pathophysiology to clinical trials.

Microglia, the resident immune cells of the central nervous system, play a pivotal role in the response to Huntington's disease (HD) pathology. Through both cell-autonomous mechanisms and exposure to external pathogenic stimuli, microglia transition from a resting to an activated state, producing pro-inflammatory cytokines and chemokines that mediate inflammation. While this inflammatory response attempts to have a neuroprotective compensatory effect, chronic microglial activation exacerbates neuroinflammation, neurodegeneration and contributes to disease progression. Evidence from postmortem analyses and neuroimaging studies indicates that activated microglia are present in various stages of HD, correlating with neuronal degeneration and clinical symptoms. Enhanced microglial activation has been identified as an early predictor of disease onset, particularly in premanifest HD, highlighting the potential of targeting microglial pathways for therapeutic interventions. This review explores microglia's dual role in HD pathophysiology, exploring their contributions to both neuroinflammation and neuroprotection. It also examines recent advances in clinical trials aimed at modulating microglial activity, paving the way for novel therapeutic strategies to alter disease progression and improve patient outcomes.