Identification of biomarkers and pathways to identify novel therapeutic targets in Alzheimers disease: Insights from a systems biomedicine perspective

Abstract

Background and objectivesAlzheimers disease (AD) is the progressive neurodegenerative disease characterized by dementia, but no peripheral biomarkers available yet that can detect the AD. This study aimed to identify systems biomarker signatures in the AD through integrative analyses.\n\nMaterials and MethodsWe used two microarray transcriptomics datasets of blood from AD patients to identify differentially expressed genes (DEGs). Geneset and protein overrepresentation analysis, protein-protein interaction (PPI), DEGs-Transcription Factor interactions, DEGs-MicroRNAs interactions, protein-drug interactions, and protein subcellular localizations analyses were done on common DEGs.\n\nResultsTotal 25 DEGs were detected between the two datasets. Integration of DEGs with biomolecular networks revealed hub proteins (TUBB, ATF3, NOL6, UQCRC1, SND1, CASP2, BTF3, INPP5K, VCAM1, and CSTF1), TFs (FOXC1, ZNF3, GEMIN7, and SMG9), miRNAs (mir-20a-5p, mir-93-5p, mir-16-5p, let-7b-5p, mir-708-5p, mir-24-3p, mir-26b-5p, mir-17-5p, mir-4270, and mir-4441). The analyses revealed candidate blood based biomarkers in the AD. We evaluated the histone modifications of the identified biomolecules. The hub genes and transcription factors (TFs) revealed that they possess several histone modification sites associated with Alzheimers disease. The protein-drug interactions revealed 10 candidate drugs consisting of antineoplastic (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), dermatologicals (Podofilox), and immunosuppressive agents (Colchicine) that may target the candidate systems biomarkers. The subcellular localization analysis revealed the interactions of the DEGs range from nucleus to plasma membrane through cytosol.\n\nConclusionsThis study presents blood based systems molecular biomarker signatures at RNA and protein levels which might be useful as peripheral biomarkers in the AD. The candidate drugs, histone modification sites, and subcellular localizations will be useful in future drug design in the AD.