Cytokine signaling convergence regulates the microglial state transition in Alzheimer's disease

Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer's disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome-IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.