Sweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis

Figure 2

Model of the role of neuronal chemokine (FKN) and neuronal cytokine (IL-34) in microglial phagocytosis and neuroprotection. Neuronal cells primary produce chemokine fractalkine (CX3CL1; FKN) and cytokine IL-34. Microglia predominantly express its receptor, CX3CR1, and colony-stimulating factor 1 receptor (CSF1R). Soluble form of FKN (sFKN) is secreted from damaged neurons and promotes microglial phagocytosis of neuronal debris through the release of MFG-E8. sFKN also induces the expression of the antioxidant enzyme HO-1 in microglia via Nrf2 recruitment and activation of the JNK MAPK signaling pathway. The neuroprotective effects of sFKN are also mediated in part by activation of ERK MAPK, although the downstream signaling pathway has not yet been elucidated. IL-34 promoted microglial proliferation and clearance of Aβ which mediates insulin-degrading enzyme (IDE) expression. Therefore, sFKN and IL-34 may be an intrinsic neuroprotectant for damaged yet surviving neurons.