IL-4 in Alzheimer's Disease-Mechanisms and Therapeutic Potential

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological hallmarks of amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. Neuroinflammation, driven largely by glial cells, is now recognized as a critical player in AD pathogenesis, contributing to both initiation and progression. Recent studies have indicated that interleukin-4 (IL-4), an anti-inflammatory cytokine with powerful immunomodulatory functions, facilitates the resolution of neuroinflammation. However, other research findings suggest that intervention with IL-4 might also exacerbate the course of AD, which complicates the understanding of the role of IL-4 in AD. Hence, this review comprehensively examines the complex and dualistic role of IL-4 in AD. We begin by outlining the contribution of IL-4 to the innate immunity of the brain, including the biological characteristics of IL-4, the main responsive cells in the central nervous system, and the directly activated signaling pathways. Next, we explored the dualistic role of IL-4 in AD from four perspectives: its impact on the clearance of amyloid plaques, its effect on the phosphorylation of the tau protein, its regulation of neuroinflammation, and its effects on neuroprotection. Finally, we summarize the current research status of the use of IL-4 as a therapeutic target to regulate immune function, alleviate neuroinflammation, and improve AD, as well as the future challenges of this approach as a therapeutic strategy for AD.