Unravelling neuronal death mechanisms: The role of cytokines and chemokines in immune imbalance in Alzheimer’s disease progression

Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of inflammatory mediators contributes to or results from amyloid-β and tangle deposition, triggers oxidative stress, excitotoxicity, and neuroinflammation, leads to cell death through multiple mechanisms, including apoptosis, ferroptosis, pyroptosis, PANoptosis, etc. The pathogenetic mechanisms responsible for neuronal death and dysfunction in AD are not yet fully understood. This review seeks to compile evidence for the various modes of neuronal cell death in AD and to explore how the neuroinflammatory environment of the AD brain influences these distinct forms of cell death. Several inflammatory signalling cascades are involved in above discussed neuronal death mechanisms, such as RAGE/NF-κB, NLRP3 inflammasome, AMPK/mTOR/ULK1, cGAS-STING, RIPK1/RIPK3/MLKL, GPX4/Nrf2 and JAK-STAT pathways. Therapeutic drugs such as Magnolol, Necrostatin-1, Salidroside, Azeliragon, DNL788, Baricitinib, Sargramostim, etc. targeting neuroinflammation-associated signaling pathways, have shown efficacy in preclinical and clinical studies mitigating AD pathology. Enhancing our comprehension of neuronal death mechanisms could elucidate disease pathogenesis, offer insights for therapeutic approaches, and aid in developing modified animal models of AD.