Integration of genomic data and machine learning to identify signature genes in pyroptotic cell death in neural cells of AD patients

Alzheimer’s Disease is the most prevalent neurodegenerative diseases in which neural cellsdie in various ways. Pyroptosis is a cell death type which induces inflammation in neural cells in ADvia formation of inflammosome, but its regulatory mechanisms in this disease are not clear yet. Neuralcell loss leads to AD progression and no exact treatment method has been found to suppress this process.In this study, we aimed to explore the regulatory mechanisms underlying pyroptosis in AD brain tissue.For this purpose, multiple microarray datasets of AD samples were integrated and analyzed to finddifferentially expressed genes in comparison with healthy control samples. Then, ML algorithms wereused to find the signature genes via LASSO algorithm. In addition, the signature genes were used todifferentiate AD and control samples. GSEA analysis was used to find key signaling pathways.WGCNA analysis was used to find the key genes associated with this cell death. Our results revealedthat four genes including TLR۱, IL-۳۲, TAC۱, and S۱۰۰A۴ are signature genes for pyroptosis in AD.These genes are expressed differentially in AD samples compared to the control groups and can be usedto differentiate AD and control samples. GSEA analysis showed that inflammatory response, IL۶-JAKSTATSignaling, TNF-alpha signaling via NF-κB, and cytokine-cytokine receptor signaling pathwaysare closely related to the pyroptosis. WGCNA analysis yielded one cluster of mostly associated genesamong which cytokines and TLRs were main regulatory nodes in the results of protein-proteininteraction analysis. We developed a robust and novel signature for pyroptosis identification in ADbased on the machine learning algorithms and bioinformatic tools. Notably, the found genes have notbeen studied in AD as therapeutic or prognostic factors, while we found them to be effective signaturegenes with potential role in regulation of pyroptosis in AD.

کلیدواژه ها:

Alzheimer’s Disease ، pyroptosis ، machine learning ، signature gene