Figure 1.

Schematic illustration indicates the role of the microglial NF-κB, NLRP3, TREM2, and cGAS-STING in Alzheimer’s disease. Aβ triggers the activation of the NF-κB pathway and NLRP3 inflammasome, leading to inflammatory cytokine release and promoting the pyroptotic death of neurons. TREM2 pairs with DAP12 through charge interactions in the transmembrane domain. Aβ and lipid proteins are the main binding ligands on the TREM2 receptor. Upon binding, DAP12 gets phosphorylated and recruits spleen tyrosine kinase (SYK), which initiates a cascade of signaling events, including phosphoinositide 3-kinase (PI3K) activation, that targets AKT and then activates mammalian target of rapamycin (mTOR), leading to inhibition of autophagy and degradation of Aβ. Foreign or mt DNA activates cGAS, which synthesizes the second messenger cGAMP from ATP and GTP. cGAMP binds to STING, leading to downstream activation of transcription factors for type I IFNs and proinflammatory cytokines that modulate neuroinflammation to produce an immune response against the pathogenic entity.