Mechanistic insights into elevated caspase-8 expression driving caspase-3 activation and Gasdermin E-dependent...

This study aims to investigate the specific mechanism by which caspase-8 regulates pyroptosis through Gasdermin E (GSDME) in Alzheimer's disease (AD). By analyzing the expression level of caspase-8 in AD pathology and its impact on pyroptosis and neuroinflammation, we aim to elucidate the role of caspase-8 as a potential therapeutic target and provide new insights into the pathological research and treatment strategies for AD.

We utilized GEO2R to analyze the GSE48350 and GSE118553 datasets, identifying differential genes in AD and exploring the pathways involved through GO and KEGG enrichment analyses. The expression patterns of caspase-8 in different tissues and cells were analyzed using the HPA and UCSF databases. RT-qPCR and Western blot techniques were employed to detect the expression of caspase-8 and caspase-3 in AD cellular models. By knocking down caspase-8 and caspase-3, we observed their effects on the expression of pyroptosis-related proteins and inflammatory cytokines.

This study is the first to systematically reveal that caspase-8 is significantly upregulated in AD and induces pyroptosis by activating caspase-3, which mediates GSDME cleavage. In AD cellular models, knockdown of caspase-8 resulted in significant reductions in pyroptosis and cell death. Moreover, knockdown of caspase-3 significantly decreased the cleavage of GSDME and the expression of inflammatory cytokines IL-1β and IL-18.

This study demonstrates that caspase-8 is significantly upregulated in Alzheimer's disease (AD) and exacerbates neuroinflammation and cell death through the activation of caspase-3 and Gasdermin E (GSDME)-dependent pyroptosis. Inhibition of caspase-8 effectively alleviates AD pathological changes, highlighting its potential as a therapeutic target.