Unraveling the cGAS-STING pathway in Alzheimer's disease: A new Frontier in neuroinflammation and therapeutic strategies.

Alzheimer's disease (AD) is the most prevalent type of neurological disorder characterized by cognitive decline and memory loss, marked by the accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein, causing extensive neuronal death and neuroinflammation. There is growing evidence that AD development extends beyond the neuronal compartment and has a major impact on the immunological functions of the brain. The cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA, including pathogenic foreign DNA and self-DNA from cellular injury, triggering a type I interferon (IFN-I) response through activation of the stimulator of interferon genes (STING). The activation of the cGAS-STING pathway in response to mitochondrial dysfunction drives neuroinflammation in AD, which is mediated by the release of IFN-I cytokines. Furthermore, the release of oxidized mtDNA is necessary for the stimulation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, which is a family of protein complexes that macrophages can produce to induce inflammation. AD becomes severe by the stimulation of the cGAS-STING pathway, which results in sterile inflammation and microglial dysfunction. This review aims to explore the potential impact of the cGAS-STING signaling pathway in the pathogenesis and progression of AD. Additionally; after overviewing recent findings, this article highlights the molecular mechanism involved in the onset of disease and its modulation regarding the therapeutic approach of AD. Finally, deliberated a deep insight, the cGAS-STING axis could provide novel therapeutic avenues for slowing or halting the progression of AD, thereby offering new prospects for treatment development.