IL-18 binding protein attenuates neuroinflammation and cognitive decline in Alzheimer's disease.

Neuroinflammation in Alzheimer’s disease (AD) extends beyond a secondary response to amyloid-β plaques and neurofibrillary tangles, representing a fundamental driver of disease pathogenesis. The NLRP3 inflammasome has emerged as a central mediator of neuroinflammation in AD, highlighting the importance of understanding its downstream effectors. Interleukin-18 (IL-18), a key proinflammatory cytokine activated by NLRP3 inflammasome, plays a crucial role in innate immunity and neuroinflammatory responses in neurodegenerative diseases and aging. However, its specific contribution to AD pathogenesis remains poorly understood. IL-18 binding protein (IL-18 BP), an endogenous inhibitor that suppresses IL-18-mediated inflammatory responses including IFNγ production, presents a potential therapeutic molecule, yet its regulatory role in AD has not been thoroughly investigated. This study aims to examine whether IL-18 and IL-18 BP are associated with neuroinflammation and neurodegeneration in AD progression and investigate the preventive effects of IL-18 BP in AD. Employing postmortem brain tissues of AD patients and AD mouse models, we confirmed that IL-18 and related proinflammatory signaling were activated in the absence of IL-18 BP in both AD patients and mice, including C/EBPβ transgenic mice, 3xTG (APP Swedish, MAPT P301L, PSEN1M146V), and 5xFAD (familial AD mutation) mice. Administration of IL-18 BP into the hippocampus alleviated inflammation and cognitive impairment during AD pathology progression in 3xTG mice compared to the vehicle administration group. These results suggest that IL-18 BP might be a new target for AD prevention by regulating IL-18-induced proinflammatory reactions and AD pathologies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03720-7.