The role of melatonin in amyloid beta-induced inflammation mediated by inflammasome signaling in neuronal cell lines

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In addition to amyloid beta (A beta) and tau, neuroinflammation is a crucial element in the etiology of this disease. However, the relevance of inflammasome-induced pyroptosis to AD is unknown. We aimed to clarify whether the anti-inflammatory effects of melatonin could prevent A beta-mediated activation of the inflammasome. We demonstrated that A beta upregulated NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD, and cysteinyl aspartate-specific proteinase caspase (caspase 1) expression in SH-SY5Y neuroblastoma cells, resulting in the release of proinflammatory cytokines, including interleukin-1 beta (IL-1 beta), interleukin-18 (IL-18) and tumor necrosis factor (TNF-alpha). Melatonin prevented inflammasome signaling and excessive cytokine release caused by A beta. We found that ethyl 2[(2-chlorophenyl)(hydroxy) methyl]acrylate (INF-4E, NLRP3 and caspase 1 inhibitor) significantly abolished A beta-induced proinflammatory cytokine expression. The increase in cleaved-caspase 1, pro-IL18, and cleaved-IL18 caused by A beta suggested the occurrence of pyroptosis, which was further confirmed by the increased expression of N-terminal gasdermin D (N-GSDMD). Melatonin plays a protective role against A beta-induced inflammation via an inflammasome-associated mechanism that is essential in inducing the active forms of cytokines and pyroptosis. The ability of melatonin to inhibit inflammasome may represent a turning point in the treatment of AD progression.

Automated summary

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and inflammation plays a crucial role in its development. This study discovered that melatonin, through its anti-inflammatory effects, can prevent the activation of the inflammasome caused by amyloid beta (A beta) and reduce the release of proinflammatory cytokines and the occurrence of pyroptosis. The ability of melatonin to inhibit the inflammasome may have implications for the treatment of AD.