From Genes to Metabolites: HSP90B1's Role in Alzheimer's Disease and Potential for Therapeutic Intervention

Alzheimer's disease (AD) is a prototypical neurodegenerative disorder, predominantly affecting individuals in the presenile and elderly populations, with an etiology that remains elusive. This investigation aimed to elucidate the alterations in anoikis-related genes (ARGs) in the AD brain, thereby expanding the repertoire of biomarkers for the disease. Using publically available gene expression data for the hippocampus from both healthy and AD subjects, differentially expressed genes (DEGs) were identified. Subsequent intersection with a comprehensive list of 575 ARGs yielded a subset for enrichment analysis. Machine learning algorithms were employed to identify potential biomarker, which was validated in an AD animal model. Additionally, gene set enrichment analysis was conducted on the biomarker and its interacting genes and microRNAs were predicted through online databases. To assess its biological functions, the expression of the marker was suppressed in an in vitro model to examine cell viability and inflammation-related indicators. Furthermore, following treatment with the inhibitor, the dysregulated metabolites in the hippocampus of the model mice were evaluated. Forty-seven ARGs were ultimately identified, with HSP90B1 emerging as a central marker. HSP90B1 was found to be significantly up-regulated in AD hippocampal samples and its inhibition conferred increased cell viability and reduced levels of inflammatory factors in amyloid β-protein (Aβ)-treated cells. A total of 24 differentially expressed metabolites were confidently identified between model mice and those with low HSP90B1 expression, with bioinformatics analysis shedding light on the molecular underpinnings of HSP90B1's involvement in AD. Collectively, these findings may inform novel insights into the pathogenesis, mechanisms, or therapeutic strategies for AD.