Fig. 1
CX3CR1/ Fractalkine signalling—different roles in Microglia: In Alzheimer’s disease, chronic neuroinflammation increases the pro-inflammatory stimuli such as LPS, TNF-α and IL-6 in the CNS. Microglial cells, which are maintained at the resting stage under normal conditions, are activated by these pro-inflammatory stimuli by interacting through several surface receptors. Upon pro-inflammatory activation, microglia release excess of pro-inflammatory cytokines in the environment to activate more microglial cells to target the site of inflammation. Pro-inflammatory cytokine, IL-1β secreted from inflammatory microglia activates the TLR4 signalling pathway of neuronal cells and is involved in hyperphosphorylation of Tau protein by activating p38 MAP kinases. Fractalkine (CX3CL1), constitutively expressed neuronal protein, is either present as soluble or membrane-bound maintains the microglia in a quiescent stage. The pro-inflammatory TNF-α secretion by the microglial cells activates TNF receptors of neuronal cells and promotes the expression of fractalkine. Fractalkine interacts with CX3CR1 and activates Gi protein-mediated signalling pathway that activates nuclear transcription factors, NFκB and NRF2. CX3CR1/CX3CL1 activation also inhibits pro-inflammatory cytokine synthesis and microglial activation. In AD conditions, misfolded Tau aggregated to form oligomers and filaments that spread across the CNS. Also, the extracellular Tau interacts with CX3CR1 for its internalization