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

Published on April 15, 2022

Imagine you’re trying to navigate a sprawling city, and you stumble upon a hidden map that reveals the intricate connections between all its neighborhoods. That’s exactly what scientists did with Alzheimer’s disease (AD). By analyzing the molecular network within the human brain, they uncovered two crucial modules filled with genes linked to AD. These modules, known as M3 and M8, showed significant dysregulation in both normal aging and AD. Further analysis revealed that neurons were particularly vulnerable in the progression of AD. Using a powerful screening tool called Connectivity Map, researchers discovered a potential drug candidate: Gly-His-Lys acetate salt (GHK). This candidate could possibly restore the dysregulated genes within the M3 and M8 network. Excitingly, laboratory experiments demonstrated that GHK had a neuroprotective effect against amyloid-beta-induced injury in human neuron-like cells. This groundbreaking study paves the way for novel approaches to combat AD by targeting the intricate molecular network that underlies the disease. If you’re eager to dive into the details of this research and unravel the mysteries of AD, check out the full article!

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.

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