Discovery of Novel Drug Candidates for Alzheimer’s Disease by Molecular Network Modeling

• Main Authors: Li, Q. (Author), Lu, Y. (Author), Wang, Z. (Author), Wu, W. (Author), Zhang, X. (Author), Zhao, H. (Author), Zhou, J. (Author), Zuo, Z. (Author)
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2022
• Subjects: aging; Alzheimer’s disease; co-expressed modules; drug repurpose; transcriptomic analysis
• Online Access: View Fulltext in Publisher

 To identify the molecular mechanisms and novel therapeutic agents of late-onset Alzheimer’s disease (AD), we performed integrative network analysis using multiple transcriptomic profiles of human brains. With the hypothesis that AD pathology involves the whole cerebrum, we first identified co-expressed modules across multiple cerebral regions of the aging human brain. Among them, two modules (M3 and M8) consisting of 1,429 protein-coding genes were significantly enriched with AD-correlated genes. Differential expression analysis of microarray, bulk RNA-sequencing (RNA-seq) data revealed the dysregulation of M3 and M8 across different cerebral regions in both normal aging and AD. The cell-type enrichment analysis and differential expression analysis at the single-cell resolution indicated the extensive neuronal vulnerability in AD pathogenesis. Transcriptomic-based drug screening from Connectivity Map proposed Gly-His-Lys acetate salt (GHK) as a potential drug candidate that could probably restore the dysregulated genes of the M3 and M8 network. Pretreatment with GHK showed a neuroprotective effect against amyloid-beta-induced injury in differentiated human neuron-like SH-SY5Y cells. Taken together, our findings uncover a dysregulated network disrupted across multiple cerebral regions in AD and propose pretreatment with GHK as a novel neuroprotective strategy against AD. Copyright © 2022 Zhou, Li, Wu, Zhang, Zuo, Lu, Zhao and Wang.