Targeting cytokine-driven neuroinflammation in Alzheimer's disease: mechanistic insights and pharmacological strategies.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. Although the classical pathological hallmarks of AD include extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence indicates that neuroinflammation plays a central role in disease initiation and progression. Among the key mediators of neuroinflammatory responses, cytokines have emerged as critical regulators of immune communication within the central nervous system. Activated microglia and reactive astrocytes release a wide range of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and interferon-γ, which contribute to synaptic dysfunction, neuronal injury, and amplification of inflammatory signaling pathways. Conversely, anti-inflammatory cytokines such as interleukin-10, interleukin-4, and transforming growth factor-β participate in regulating immune homeostasis and may exert neuroprotective effects by suppressing excessive inflammatory responses. This review provides a comprehensive overview of cytokine-mediated neuroinflammation in Alzheimer's disease, focusing on the cellular sources of cytokine production within the brain, including microglia, astrocytes, neurons, and endothelial cells. Key intracellular signaling pathways involved in cytokine activity, such as nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and mitogen-activated protein kinase (MAPK) pathways, are also discussed in relation to their roles in inflammatory amplification and neurodegeneration. Furthermore, the complex interactions between cytokine signaling, amyloid-β accumulation, and tau pathology are examined to highlight the interconnected mechanisms underlying disease progression. Finally, emerging therapeutic strategies targeting cytokine-driven neuroinflammatory pathways are explored, emphasizing their potential in the development of novel anti-inflammatory and disease-modifying treatments for Alzheimer's disease.