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

Abstract

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.

Neuropathological stage‐dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory‐related omics signatures to computational repurposing of drug candidates

“…However, downstream events associated to apoptosis, proliferation, differentiation, and inflammation are highly represented in CMap, opening the door to novel combinations that might trigger the multilevel downstream signals beyond the synaptic plasticity. In fact, similar workflows employing transcriptomic profiles [ 43 , 44 , 45 ], gene coexpression networks [ 46 ], molecular network modeling [ 47 ], and protein–protein interaction networks [ 48 ] have been used to discover novel drug candidates for AD as well as for other neurological syndromes [ 49 , 50 ]. Nevertheless, few studies developed further in vitro and/or in vivo validation for computational drug repurposing predictions [ 45 , 47 ].…”

Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheime’s disease: From early olfactory-related omics signatures to computational repurposing of drug candidates

“…However, downstream events associated to apoptosis, proliferation, differentiation and inflammation are highly represented in Cmap, opening the door to novel combinations that might trigger the multilevel downstream signals beyond the synaptic plasticity. In fact, similar workflows employing transcriptomic profiles (40)(41)(42), gene coexpression networks (43), molecular network modeling (44) and protein-protein interaction networks (45) have been used to discover novel drug candidates for AD as well as for other neurological syndromes (46,47). Nevertheless, few studies developed further in vitro and/or in vivo validation for computational drug repurposing predictions (42,44).…”

“…In fact, similar workflows employing transcriptomic profiles (40)(41)(42), gene coexpression networks (43), molecular network modeling (44) and protein-protein interaction networks (45) have been used to discover novel drug candidates for AD as well as for other neurological syndromes (46,47). Nevertheless, few studies developed further in vitro and/or in vivo validation for computational drug repurposing predictions (42,44). Our rationale was based on the discovery of compounds/small molecules with capacity to restore the initial imbalance in olfactory metabolism leading to block the progressive neuropathological alterations that accompany the cognitive impairment.…”

Atorvastatin and Nitrofurantoin Repurposed in the Context of Breast Cancer and Neuroblastoma Cells

“…Indeed, the MCF-7 cell line is the most studied human breast cancer cell line in the world [ 18 ]. In fact, drug repurposing studies are frequently performed in these two cell lines [ 19 , 20 ].…”