Targeting the chemokine-microglia nexus: A novel strategy for modulating neuroinflammation in Alzheimer's disease

An increasing body of evidence suggests neuroinflammation has a prominent role in the pathogenesis of Alzheimer's disease (AD). The amyloid-β-tau-neurodegeneration (ATN) classification system is now being expanded toward an amyloid-β-tau neurodegeneration-neuroinflammation (ATN(I)) system. Activated microglia and reactive astrocytes are the key hubs for neuroinflammation in AD, and chemokines are recognized as pivotal modulators of microglial innate immune functions. In this review, based on the chemokine-microglia regulatory axis, we elucidate the mechanisms through which chemokines influence microglial function, potentially modulating neurotoxicity or neuroprotection in AD. The key chemokines that significantly affect microglial polarization, such as CCL2, CCL3, and CXCL1, are summarized, and their role in disease progression are elaborated. Additionally, we explore prospective therapeutic interventions centered on the chemokine-microglia regulatory axis, offering valuable perspectives on pathobiology of AD and avenues for pharmacological advancements.