Imagine Alzheimer’s disease as a lock and quercetin as the key that can unlock potential therapeutic targets. Researchers used network pharmacology to identify the intersection genes of quercetin and Alzheimer’s disease, aiming to uncover new approaches to treatment. By studying the pharmacological targets of quercetin, analyzing gene expressions in the frontal cortex of Alzheimer’s patients, and exploring drug screening databases, they found 207 genes related to quercetin’s effects in AD. These genes were involved in processes like axonogenesis and glial differentiation. Additionally, there were 155 immune-related genes and 65 cortex-related genes targeted by quercetin. The study also linked these genes to AD severity scores and identified various miRNAs associated with quercetin’s impact on cognitive function. Further experiments confirmed the regulation of six out of twelve selected genes by quercetin. DYRK1A, NOS2, and NQO1 showed potential as effective quercetin drug targets for treating AD, while FOXO1, NGF, and RORA may have a negative impact. This research sheds light on the multifaceted role of quercetin in AD treatment and offers new insights into potential therapeutic pathways.

BackgroundCurrently, there are no efficient therapies for Alzheimer’s disease (AD) among the elderly, although it is the most common etiology of dementia among the elderly. Quercetin, which has a variety of therapeutic properties, may pave the way for novel approaches to AD treatment. In the AD patients’ frontal cortex, current study aims to identify the potential mechanisms of quercetin’s pharmacological targets.Materials and methodsThe pharmacological targets of quercetin have been studied from DrugBank and SwissTarget. In order to distinguish AD-associated genes targeted by quercetin (Q-ADGs), we utilized an integrated intersection of gene expressions of the frontal cortex in combination with transcriptome analysis. To detect cortex-related Q-ADGs and immune-related Q-ADGs, a drug screening database and the immune infiltration analysis was utilized. The Q-ADGs were then linked with the AD severity scores (MMSE scores) to find severity-associated Q-ADGs. In addition, the miRNA-seq datasets were examined to identify severity-associated Q-ADG-miRNAs. Twelve genes, more frequently related to AD by previous studies among all the genes identified in the present study, were subjected to the verification of qRT-PCR in AD cell model.ResultsIn the frontal lobe of AD, 207 Q-ADGs were discovered and found that axonogenesis, glial differentiation, and other biological processes had been enriched. There were 155 immune-related Q-ADGs (e.g., COX2, NOS2, HMGB1) and 65 cortex-related Q-ADGs (e.g., FOXO1, CXCL16, NOTCH3). Sixteen Q-ADGs (e.g., STAT3, RORA, BCL6) and 28 miRNAs (e.g., miR-142-5p, miR-17-5p) were found to be related to MMSE scores. In the qRT-PCR results, six out of twelve genes were significantly regulated by quercetin. DYRK1A, FOXO1, NOS2, NGF, NQO1, and RORA genes were novel target of quercetin in AD. DYRK1A, NOS2, and NQO1 genes targeted by quercetin have benefits in the treatment of AD. However, FOXO1, NGF, and RORA genes targeted by quercetin might have a negative impact on AD.ConclusionThe role of quercetin in AD appears to be multifaceted, and it can affect patients’ frontal cortex in a variety of pathways, such as axonogenesis, immune infiltration, and glial cell differentiation. DYRK1A, NOS2, and NQO1 might be potential novel effective drug targets for quercetin in AD.

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