Identifying endoplasmic reticulum stress-related key genes of vascular dementia using bioinformatics and biological experiments.

Vascular dementia (VaD) is the second most common type of dementia, yet its pathogenesis is not fully understood, and effective diagnostic and therapeutic tools are lacking. While endoplasmic reticulum stress (ERS) is associated with VaD and is recognised as a promising target, the exact mechanism remains unclear. This study analysed differentially expressed ERS-related genes in VaD to identify potential diagnostic markers and provide a new perspective for further in-depth research on the role of ERS in VaD. VaD gene expression data (GSE186798) from human patients were obtained from the GEO database for analysis. After intersecting the obtained genes with those in the GeneCards and Molecular Signatures Databases (MSigDB), key ERS-related genes for the diagnosis of VaD were identified as hub genes using bioinformatics and machine learning techniques. Two hub genes, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PPARGC1A) and SEC61 Translocon Subunit Gamma (SEC61G), exhibited good diagnostic ability for VaD and were validated in the GSE122063 dataset using receiver operating characteristic (ROC) curve analysis. GeneMANIA analysis indicated a robust association between VaD pathophysiology and ERS responses. Hub genes regulated by microRNAs, transcription factors, and chemicals were computationally predicted, and immune cells with varying dysregulation were also observed. In an in vivo bilateral common carotid artery stenosis (BCAS) mouse model, quantitative real-time PCR (qRT-PCR) and Western blotting analyses confirmed the significant downregulation of the hub genes' expression levels. These hub genes may serve as potential diagnostic biomarkers for VaD.