Identification of oxidative stress-related genes differentially expressed in Alzheimer’s disease and construction of a hub gene-based diagnostic model

Abstract

Alzheimer’s disease (AD) is the most prevalent dementia disorder globally, and there are still no effective interventions for slowing or stopping the underlying pathogenic mechanisms. There is strong evidence implicating neural oxidative stress (OS) and ensuing neuroinflammation in the progressive neurodegeneration observed in the AD brain both during and prior to symptom emergence. Thus, OS-related biomarkers may be valuable for prognosis and provide clues to therapeutic targets during the early presymptomatic phase. In the current study, we gathered brain RNA-seq data of AD patients and matched controls from the Gene Expression Omnibus (GEO) to identify differentially expressed OS-related genes (OSRGs). These OSRGs were analyzed for cellular functions using the Gene Ontology (GO) database and used to construct a weighted gene co-expression network (WGCN) and protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were then constructed to identify network hub genes. A diagnostic model was established based on these hub genes using Least Absolute Shrinkage and Selection Operator (LASSO) and ROC analyses. Immune-related functions were examined by assessing correlations between hub gene expression and immune cell brain infiltration scores. Further, target drugs were predicted using the Drug-Gene Interaction database, while regulatory miRNAs and transcription factors were predicted using miRNet. In total, 156 candidate genes were identified among 11046 differentially expressed genes, 7098 genes in WGCN modules, and 446 OSRGs, and 5 hub genes (MAPK9, FOXO1, BCL2, ETS1, and SP1) were identified by ROC curve analyses. These hub genes were enriched in GO annotations “Alzheimer’s disease pathway,” “Parkinson’s Disease,” “Ribosome,” and “Chronic myeloid leukemia.” In addition, 78 drugs were predicted to target FOXO1, SP1, MAPK9, and BCL2, including fluorouracil, cyclophosphamide, and epirubicin. A hub gene-miRNA regulatory network with 43 miRNAs and hub gene-transcription factor (TF) network with 36 TFs were also generated. These hub genes may serve as biomarkers for AD diagnosis and provide clues to novel potential treatment targets.

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer’s disease

“…Moreover, in longitudinal studies, either the number of samples has been low, thus limiting the depth of the analysis, or the tissues considered have not been brain-derived. In any case, the previous studies enabled us to identify not only relevant pathways associated with AD pathology but also gene candidates that can drive the pathology or be employed as biomarkers (Hu et al, 2020; Miller et al, 2008; Soleimani Zakeri et al, 2020; Sun et al, 2022; Upadhyaya et al, 2020; Zhang and Kiryu, 2023). Here, the dataset employed provided transcriptomic data of early, intermediate and late AD stages identified via integration of several pathological parameters.…”

Dementia and depression: Biological connections with amyloid β protein

“…27 Gene expression mapping in AD patients showed a profile highly associated with oxidative stress, with genes related to immune exhaustion, damage to transcription factors and mutations in genes promoting protective responses. 28 It has been reported that rats with depressive-like behaviours induced by Aβ have decreased levels of serotonin (5-HT) and norepinephrine (NA) and, in contrast, increased levels of tryptophan (TRP) and kynurenine (KYN) and high concentrations of ROS in the PFC, and consequent establishment of a neuroinflammatory state with local tissue damage (Figure 2). Pharmacotherapy aimed at inhibiting IDO has demonstrated efficacy in controlling depression, reversing 5-HT levels and oxidative stress in animal models exposed to the accumulation of amyloid-β protein.…”

“…Imaging methods showed increased oxidative damage due to Aβ deposition associated with lower glutathione and superoxide dismutase (SOD) activity in a mice model to study AD 27 . Gene expression mapping in AD patients showed a profile highly associated with oxidative stress, with genes related to immune exhaustion, damage to transcription factors and mutations in genes promoting protective responses 28 …”

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer’s Disease

“…The production of ROS can be significantly increased by several pathogenic conditions, including inflammation, metal dyshomeostasis, and mitochondrial dysfunction by various environmental traumas (such as infections, UV, or heat exposure). , This condition is cumulatively called as oxidative stress. , Oxidative stress is a state of imbalance between the production of reactive oxygen/nitrogen species (ROS/RNS) and the capacity of antioxidants to remove these toxic species from the body. Increased oxidative stress is thought to be linked to one of the earliest steps in the onset of neurodegeneration in AD. , Therefore, molecules exhibiting promising antioxidant properties are supposed to offer hope against AD, where free radicals play a key role in the disease progression.…”

“…Increased oxidative stress is thought to be linked to one of the earliest steps in the onset of neurodegeneration in AD. 20,21 Therefore, molecules exhibiting promising antioxidant properties are supposed to offer hope against AD, where free radicals play a key role in the disease progression.…”