Systemic inflammasome activation and pyroptosis associate with the progression of amnestic mild cognitive impairment and Alzheimer's disease

Background: Growing evidence indicates that inflammasome-mediated inflammation plays important roles in the pathophysiology of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Pyroptosis induced by inflammasome, and Gasdermin D (GSDMD) is involved in several neurodegenerative disorders. However, it is not clear whether peripheral inflammasome and pyroptosis are activated in aMCI and AD patients, influencing on neuroinflammation. The aim of this study was to examine the association between systemic inflammasome-induced pyroptosis and clinical features in aMCI and AD. Methods: A total of 86 participants, including 33 subjects with aMCI, 33 subjects with AD, and 20 cognitively normal controls, in this study. The Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scale were used for cognitive assessment. Levels of inflammasome-related genes/proteins in peripheral blood mononuclear cells (PBMCs) were determined using quantitative polymerase chain reaction and Western blotting. The levels of IL-1 beta, A beta 1-42, A beta 1-40, p-tau, and t-tau in cerebrospinal fluid (CSF), as well as the plasma IL-1 beta level, were measured by enzyme-linked immunosorbent assay. Finally, lipopolysaccharides (LPS) were used to investigate the effects of systemic inflammasome-induced pyroptosis in an AD mice model. Results: Several genes involved in the inflammatory response were enriched in PBMCs of AD patients. The mRNA and protein levels of NLRP3, caspase-1, GSDMD, and IL-1 beta were increased in PBMCs of aMCI and AD patients. The IL-1 beta level in plasma and CSF of aMCI and AD patients was significantly higher than that in controls and negatively correlated with the CSF A beta 1-42 level, as well as MMSE and MoCA scores. Furthermore, there was a positive correlation between the IL-1 beta level in plasma and CSF of aMCI or AD patients. In vivo experiments showed that systemic inflammasome-induced pyroptosis aggravated neuroinflammation in 5 x FAD mice. Conclusions: Our findings showed that canonical inflammasome signaling and GSDMD-induced pyroptosis were activated in PBMCs of aMCI and AD patients. In addition, the proinflammatory cytokine IL-1 beta was strongly associated with the pathophysiology of aMCI and AD. As such, targeting inflammasome-induced pyroptosis may be a new approach to inhibit neuroinflammation in aMCI and AD patients.

Automated summary

The study revealed that canonical inflammasome signaling and GSDMD-induced pyroptosis were activated in PBMCs of aMCI and AD patients. Additionally, the proinflammatory cytokine IL-1 beta was strongly associated with the pathophysiology of aMCI and AD.