Dataset Information

Drug repurposing using meta-analysis of gene expression in Alzheimer's disease.

ABSTRACT:

Introduction

Alzheimer's disease and other forms of dementia are disease that bring an increased global burden. However, the medicine developed to date remains limited. The purpose of this study is to predict drug repositioning candidates using a computational method that integrates gene expression profiles on Alzheimer's disease and compound-induced changes in gene expression levels.

Methods

Gene expression data on Alzheimer's disease were obtained from the Gene Expression Omnibus (GEO) and we conducted a meta-analysis of their gene expression levels. The reverse scores of compound-induced gene expressions were computed based on the reversal relationship between disease and drug gene expression profiles.

Results

Reversal genes and the candidate compounds were identified by the leave-one-out cross-validation procedure. Additionally, the half-maximal inhibitory concentration (IC50) values and the blood-brain barrier (BBB) permeability of candidate compounds were obtained from ChEMBL and PubChem, respectively.

Conclusion

New therapeutic target genes and drug candidates against Alzheimer's disease were identified by means of drug repositioning.

SUBMITTER: Jang HY

PROVIDER: S-EPMC9684643 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Drug repurposing using meta-analysis of gene expression in Alzheimer's disease.

Jang Ha Young HY Oh Jung Mi JM Kim In-Wha IW

Frontiers in neuroscience 20221110

<h4>Introduction</h4>Alzheimer's disease and other forms of dementia are disease that bring an increased global burden. However, the medicine developed to date remains limited. The purpose of this study is to predict drug repositioning candidates using a computational method that integrates gene expression profiles on Alzheimer's disease and compound-induced changes in gene expression levels.<h4>Methods</h4>Gene expression data on Alzheimer's disease were obtained from the Gene Expression Omnibu ...[more]

PMID: 36440278

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Project description:Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of cognitive decline. The alarming epidemiological features of Alzheimer's disease, combined with the high failure rate of candidate drugs tested in the preclinical phase, impose more intense investigations for new curative treatments. NRF2 (Nuclear factor-erythroid factor 2-related factor 2) plays a critical role in the inflammatory response and in the cellular redox homeostasis and provides cytoprotection in several diseases including those in the neurodegeneration spectrum. These roles suggest that NRF2 and its directly associated proteins may be novel attractive therapeutic targets in the fight against AD. In this study, through a systemics perspective, we propose an in silico drug repurposing approach for AD, based on the NRF2 interactome and regulome, with the aim of highlighting possible repurposed drugs for AD. Using publicly available information based on differential expressions of the NRF2-neighborhood in AD and through a computational drug repurposing pipeline, we derived to a short list of candidate repurposed drugs and small molecules that affect the expression levels of the majority of NRF2-partners. The relevance of these findings was assessed in a four-step computational meta-analysis including i) structural similarity comparisons with currently ongoing NRF2-related drugs in clinical trials ii) evaluation based on the NRF2-diseasome iii) comparison of relevance between targeted pathways of shortlisted drugs and NRF2-related drugs in clinical trials and iv) further comparison with existing knowledge on AD and NRF2-related drugs in clinical trials based on their known modes of action. Overall, our analysis yielded in 5 candidate repurposed drugs for AD. In cell culture, these 5 candidates activated a luciferase reporter for NRF2 activity and in hippocampus derived TH22 cells they increased NRF2 protein levels and the NRF2 transcriptional signatures as determined by increased expression of its downstream target heme oxygenase 1. We expect that our proposed candidate repurposed drugs will be useful for further research and clinical translation for AD.

Dataset Information

Drug repurposing using meta-analysis of gene expression in Alzheimer's disease.

Introduction

Methods

Results

Conclusion

Publications

Drug repurposing using meta-analysis of gene expression in Alzheimer's disease.

Similar Datasets

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