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Figure 4. Molecular mechanisms and signaling pathways in AD. Multiple signaling pathways contribute to AD pathology, particularly those linked to neuroinflammation, neuronal death, and Aβ deposition. (1) cGAS-STING pathway: Cytosolic leakage of mtDNA or self-DNA activates cGAS, generating cGAMP that binds STING. This triggers TBK1-mediated IRF3 phosphorylation and NF-κB activation (via IκBα degradation and p65/p50 nuclear translocation), inducing type I interferons and proinflammatory cytokines (e.g., TNF-α, IL-6); (2) NLRP3 inflammasome pathway: DAMPs (e.g., Aβ fibrils) activate NLRP3, promoting ASC speck formation and caspase-1 cleavage. Activated caspase-1 converts pro-IL-1β into its mature form, amplifying neuroinflammation. This process is influenced by mitochondrial and lysosomal dysfunction and regulated by post-translational modifications; (3) TREM2 signaling: Aβ plaques engage TREM2 receptors on microglia, initiating SYK/PI3K/AKT phosphorylation cascades that enhance phagocytosis (Aβ/tau clearance) and support microglial survival. Dysregulated TREM2 impairs these functions, exacerbating plaque accumulation. Crosstalk among these pathways creates feed-forward loops that reinforce glial activation, neuronal damage, and further Aβ production. [Created in BioRender. 1, 1. (2025) https://BioRender.com/x4z0nw6]. AD: Alzheimer’s disease; Aβ: amyloid-β; cGAS: cyclic GMP-AMP synthase; STING: stimulator of interferon genes; mtDNA: mitochondrial DNA; cGAMP: 2’,3’-cyclic GMP-AMP; NF-κB: nuclear factor-κB; NLR: NOD-like receptor; NLRP3: NLR family pyrin domain containing 3.