Systemic Inflammasome Activation and Pyroptosis Associate with the Progression of Alzheimer’s Disease

Abstract Background: Growing evidence indicates that inflammasome-mediated inflammation plays an important role in the pathophysiology of Alzheimer’s disease (AD). Likewise, gasdermin D (GSDMD) as executive molecule in inflammasome-induced pyroptosis is also involved in many neurological disorders. However, it is not clear whether inflammasome and pyroptosis is activated in the periphery of AD patients and influences central inflammation. The aim of this study was to evaluate the association between systemic inflammasome-induced pyroptosis and clinical features in the progression of AD.Methods: A total of 86 participants, including 33 patients with AD, 33 patients with amnestic mild cognitive impairment (aMCI), and 20 controls, were included in this study. The cognitive level of each participant was evaluated, including Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were assigned. We collected blood samples from each participant. Gene transcriptomes of peripheral blood mononuclear cells (PBMCs) were determined by RNA-seq. The expression levels of inflammasome-related genes/proteins in PBMCs were determined using quantitative polymerase chain reaction and western blotting. Cerebrospinal fluid (CSF) samples were collected from all AD patients. The levels of IL-1β, Aβ1-42, p-tau, and t-tau in CSF, as well as the plasma IL-1β level, were measured by enzyme-linked immunosorbent assay. Lastly, a low dose of lipopolysaccharides (LPS) was performed to investigate the effects of systemic pyroptosis in AD mice model.Results: Several genes involved in the inflammatory response pathway were enriched in PBMCs of AD patients. The mRNA and protein levels of NLRP3, caspase-1, GSDMD, and IL-1β were all increased in PBMCs from AD and aMCI patients. The IL-1β levels in plasma and CSF in AD and aMCI patients were significantly higher than those in controls and have a negative correlation with levels of Aβ1-42 in CSF, MMSE and MOCA scores. Furthermore, there was a positive correlation between the IL-1β level in plasma and CSF of AD or aMCI patients. In addition, animal experiments also showed that systemic pyroptosis aggravates neuroinflammation in 5×FAD mice.Conclusions: All these findings showed that the canonical inflammasome pathway and GSDMD-induced pyroptosis is activated in PBMCs from AD and aMCI patients. Proinflammatory cytokine IL-1β in periphery is highly associated with the pathological process of AD. Targeting peripheral inflammasomes and pyroptosis may be a strategy to inhibit neuroinflammation in AD.