Title:Identification of Molecular Correlations of GSDMD with Pyroptosis in
Alzheimer's Disease
Volume: 27
Issue: 14
Author(s): Tangtang Song, Yan Chen, Chen Li, Yinhui Yao, Shuai Ma, Yazhen Shang*Jianjun Cheng
Affiliation:
- Institute of Traditional Chinese Medicine, Chengde Medical College, Chengde, 067000, P.R. China
- College of
Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200,
P.R. China
Keywords:
Alzheimer's disease, bioinformatics, gasdermin D, β-amyloid 1-42, oligodendrocytes, pyroptosis.
Abstract:
Aim: An analysis of bioinformatics and cell experiments was performed to verify the relationship
between gasdermin D (GSDMD), an executive protein of pyroptosis, and Alzheimer's disease (AD).
Methods: The training set GSE33000 was utilized to identify differentially expressed genes (DEGs) in
both the AD group and control group, as well as in the GSDMD protein high/low expression group.
Subsequently, the weighted gene co-expression network analysis (WGCNA) and the least absolute
shrinkage and selection operator (LASSO) regression analysis were conducted, followed by the selection
of the key genes for the subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and
Genomes (KEGG) analyses. The association between GSDMD and AD was assessed and confirmed in
the training set GSE33000, as well as in the validation sets GSE5281 and GSE48350. Immunofluorescence
(IF) was employed to detect the myelin basic protein (MBP), a distinctive protein found in the
rat oligodendrocytes (OLN-93 cells). A range of concentrations (1-15 μmol/L) of β-amyloid 1-42
(Aβ1-42) were exposed to the cells, and the subsequent observations were made regarding cell morphology.
Additionally, the assessments were conducted to evaluate the cell viability, the lactate dehydrogenase
(LDH) release, the cell membrane permeability, and the GSDMD protein expression.
Results: A total of 7,492 DEGs were screened using GSE33000. Subsequently, WGCNA analysis identified
19 genes that exhibited the strongest correlation with clinical traits in AD. Additionally, LASSO regression
analysis identified 13 key genes, including GSDMD, AFF1, and ATOH8. Furthermore, the investigation
revealed that the key genes were associated with cellular inflammation based on GO and
KEGG analyses. Moreover, the area under the curve (AUC) values for the key genes in the training and
validation sets were determined to be 0.95 and 0.70, respectively. Significantly, GSDMD demonstrated
elevated levels of expression in AD across both datasets. The positivity of MBP expression in cells exceeded
95%. As the concentration of Aβ1-42 action gradually escalated, the detrimental effects on cells
progressively intensified, resulting in a gradual decline in cell survival rate, accompanied by an increase
in lactate dehydrogenase release, cell membrane permeability, and GSDMD protein expression.
Conclusion: The association between GSDMD and AD has been observed, and it has been found that Aβ1-42
can induce a significant upregulation of GSDMD in OLN-93 cells. This suggests that Aβ1-42 has the potential
to induce cellular pyroptosis and can serve as a valuable cellular pyroptosis model for the study of AD.
