Abstract
BackgroundGrowing 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.MethodsA 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-1β, Aβ1-42, Aβ1-40, p-tau, and t-tau in cerebrospinal fluid (CSF), as well as the plasma IL-1β 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.ResultsSeveral 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-1β were increased in PBMCs of aMCI and AD patients. The IL-1β level in plasma and CSF of aMCI and AD patients was significantly higher than that in controls and negatively correlated with the CSF Aβ1-42 level, as well as MMSE and MoCA scores. Furthermore, there was a positive correlation between the IL-1β level in plasma and CSF of aMCI or AD patients. In vivo experiments showed that systemic inflammasome-induced pyroptosis aggravated neuroinflammation in 5 × FAD mice.ConclusionsOur 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-1β 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.
Highlights
Growing evidence indicates that inflammasome-mediated inflammation plays important roles in the pathophysiology of amnestic mild cognitive impairment and Alzheimer’s disease (AD)
Inflammation‐related genes and signaling pathways are enriched in peripheral blood mononuclear cells (PBMCs) of AD patients Inflammasomes have important roles in the progression of neuroinflammation
To investigate whether a relationship exists between peripheral inflammasome activation and dementia, we first investigated changes in the gene transcriptome of PBMCs isolated from AD and controls by performing RNA-seq analysis
Summary
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 It is not clear whether peripheral inflammasome and pyroptosis are activated in aMCI and AD patients, influencing on neuroinflammation. Neuroinflammation plays important roles in several neurodegenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis, amnestic mild cognitive impairment (aMCI), and AD [5,6,7,8]. Studies have reported that chronic neuroinflammation can occur prior to Aβ and tau pathologies in AD [9] Proinflammatory cytokines, such as interleukin (IL)-1β, can drive neuroinflammation, and their levels are upregulated in the brain and cerebrospinal fluid (CSF) of AD patients [10]. There is no study on the association between IL-1β level in CSF and inflammation activation in peripheral blood mononuclear cells (PBMCs) of aMCI and AD patients
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