Figure 2.

Pathogenic proteins activate signal transduction pathways in microglia leading to NDs. In AD, Aβ can bind to TLR4/6 on microglia and induce the release of inflammatory factors (IL-1β, TNF-α, and IL-6) through the downstream MyD88/NLRP3 and NF-κB signaling pathways. It also activates TREM2 on microglia, causing DAP12 to enhance Syk and induce a cascade of protein tyrosine phosphorylation, which leads to apoptosis and myelin damage through immune pathways. For Tau protein, it can activate microglia through PQBP1/CGAS/STING pathway, and 40% NF-κB can amplify inflammatory response in this process, leading to a series of nerve damage. The rest is supplemented by TREM2/ERK/PIK3. In PD, α-syn can stimulate microglia to secrete proinflammatory cytokines, such as ROS, TNF-α, IL-1β, COX2, and iNOS through TLR/MyD88/NLRP3 pathway. It also binds to TLR2 to induce nuclear translocation of NF-κB, which triggers the production of NLRP3, pro-IL-1β and pro-IL-18, and ultimately IL-1β secretion. TLR, toll-like receptors; MyD88, myeloid differentiation factor 88; NLRP3, NOD-like receptor thermal protein domain associated protein 3; NF-κB, nuclear factor kappa-B; TREM2, triggering receptor expressed on myeloid cells 2; DAP12, TYRO protein tyrosine kinase binding protein; PQBP1, polyglutamine binding protein-1; CGAS, cyclic GMP-AMP synthase; STING, interferon gene stimulation protein; ERK, extracellular regulated protein kinases; PIK3, phosphatidylinositide 3-kinases; ROS, reactive oxygen species; COX2, cyclooxygenase 2; iNOS, inducible nitric oxide synthase.