The mtDNA-cGAS-STING pathway: linking neuroinflammation <?A3B2 pi6?>and Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disorder associated with aging, characterized clinically by progressive memory impairment and cognitive decline. The pathological hallmarks include cerebral gray matter atrophy, extracellular amyloid plaques composed of β-amyloid aggregates, and intracellular neurofibrillary tangles (NFTs) arising from hyperphosphorylated tau protein. Emerging evidence indicates that oxidative stress and mitochondrial dysfunction during AD pathology promote the release of mtDNA, resulting in activation of the cGAS-STING signaling pathway. As an evolutionarily conserved innate immune pathway, the cGAS-STING pathway demonstrates significant activation in microglia of AD patients, which contributes to neuroinflammatory responses, suppression of the phagocytic function of microglia, enhanced adhesion of neutrophils to the vascular endothelium, and ultimately exacerbates the pathogenesis of AD. Therefore, targeting the mtDNA-cGAS-STING pathway could be a potential therapeutic strategy to alleviate neurodegeneration and improve cognitive function, with the hope of providing new insights for clinical improvement of AD symptoms. This review will systematically discuss the mechanistic interplay between mtDNA leakage and cGAS-STING activation in AD pathophysiology, while critically evaluating the translational potential and clinical challenges of modulating this pathway for AD intervention.