Ferroptosis-related biomarkers for Alzheimer’s disease: Identification by bioinformatic analysis in hippocampus

Abstract

BackgroundGlobally, Alzheimer’s Disease (AD) accounts for the majority of dementia, making it a public health concern. AD treatment is limited due to the limited understanding of its pathogenesis. Recently, more and more evidence shows that ferroptosis lead to cell death in the brain, especially in the regions of the brain related to dementia.Materials and methodsThree microarray datasets (GSE5281, GSE9770, GSE28146) related to AD were downloaded from Gene Expression Omnibus (GEO) datasets. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE5281 and GSE9770 were used to identify ferroptosis-related genes, and GSE28146 was used to verify results. During these processes, protein–protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, the differentiated values of ferroptosis-related genes were determined by receiver operator characteristic (ROC) monofactor analysis to judge their potential quality as biomarkers.ResultsTwenty-four ferroptosis-related genes were obtained. Using STRING (https://cn.string-db.org/) and Cytoscape with CytoHubba, the top 10 genes (RB1, AGPAT3, SESN2, KLHL24, ALOX15B, CA9, GDF15, DPP4, PRDX1, UBC, FTH1, ASNS, GOT1, PGD, ATG16L1, SLC3A2, DDIT3, RPL8, VDAC2, GLS2, MTOR, HSF1, AKR1C3, NCF2) were identified as target genes. GO analysis revealed that response to carboxylic acid catabolic process, organic acid catabolic process, alpha-amino acid biosynthetic process and cellular amino acid biosynthetic process were the most highly enriched terms. KEGG analysis showed that these overlapped genes were enriched in p53 signaling pathways, longevity regulating pathway, mTOR signaling pathway, type 2 diabetes mellitus and ferroptosis. Box plots and violine plots were created and verified to confirm the significance of identified target genes. Moreover, ROC monofactor analysis was performed to determine the diagnostic value of identified genes. Two genes (ASNS, SESN2) were subsequently obtained. For the tow genes, STRING was used to obtain the five related genes and determined enriched GO terms and KEGG pathways for those genes.ConclusionOur results suggest that ASNS and SENS2 may serve as potential diagnostic biomarkers for AD and provide additional evidence regarding the essential role of ferroptosis in AD.

Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy

“…Additionally, mounting evidence has proved the potential involvement of mitochondria in ferroptosis, but there are still some controversies [ [45] , [46] , [47] ]. Supporting this possibility, ferroptosis is associated with dramatic function and morphological changes of mitochondria in multiple disease states, especial neurodegenerative disease [ [45] , [46] , [47] , [48] ]. In Nlrp6 KO NSPCs, the changed genes of mitochondrial function supported the disturbed metabolic pathways, such as GSH metabolism, glutaminolysis and peroxisome biogenesis, which were also associated with the ferroptotic process by GSEA analysis.…”

The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway

“…Ferroptosis is a regulatory cell death mode discovered in recent years [ 11 ]. It is driven by iron‐dependent lipid peroxidation and is the result of the imbalance of cell metabolism and redox homeostasis [ 12 ]. It can inhibit lipid peroxidation and iron death by directly consuming iron through pharmacological or genetic means.…”

Machine learning identification and immune infiltration of disulfidptosis‐related Alzheimer's disease molecular subtypes

“…The functional roles of programmed cell death‐related genes in AD development have been previously reported. For instance, genes related to cuproptosis, 13 , 14 pyroptosis, 15 and ferroptosis 16 , 17 have been used to construct prediction models for AD. However, as the underlying mechanism of disulfidptosis has been discovered, the potential link between disulfidptosis‐related genes (DRGs) and AD remains unclear.…”