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. 2022 Apr 15:14:850217.
doi: 10.3389/fnagi.2022.850217. eCollection 2022.

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

Jiaxin Zhou  1 , Qingyong Li  2 , Wensi Wu  1 , Xiaojun Zhang  1 , Zhiyi Zuo  3 , Yanan Lu  1 , Huiying Zhao  2 , Zhi Wang  1
Affiliations

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

Jiaxin Zhou et al. Front Aging Neurosci. .

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.

Keywords: Alzheimer’s disease; aging; co-expressed modules; drug repurpose; transcriptomic analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic design on how to discover Alzheimer’s disease (AD)-related modules and anti-AD drug candidates.
FIGURE 2
FIGURE 2
Preservation of co-expressed modules and identification of AD-related modules. (A–C) Preservation scores for 19 co-expressed modules in other expression datasets: (A) across multiple cerebral regions of aging human brains, (B) of human blood tissue, (C) across aging mouse cortex and hippocampus. Each dot represents a weighted gene co-expression network analysis (WGCNA) module. Dashed red and blue lines represent Zsummary = 10 and Zsummary = 5, respectively. (D) LogFC values of genes in each module between AD patients and controls. (E) Statistical significance of each module enriched with AD-correlated genes. Q-values were determined by FET p-values corrected with the Benjamini-Hocheberg method. Each dot represents a module and a dashed line means FET q = 0.05.
FIGURE 3
FIGURE 3
Functional enrichment and expression changes of M3 and M8 in normal aging and AD across multiple cerebral regions. (A) Brain cell-type enrichment for M3 and M8. The heatmap shows the one-tailed Fisher’s exact test (FET) results with BH correction for each brain cell type. Exc, excitatory neurons; Inh, inhibitory neurons; Ast, astrocytes; Mic, microglia; OPC, oligodendrocyte progenitor cell; Oli, oligodendrocytes; End, endothelial cells; Per, pericytes. (B) Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis for M3 and M8. The enrichment network shows the intra-cluster and inter-cluster similarities of enriched KEGG terms. Color code represents the cluster annotations. (C) Comparison of sample-wise gene set enrichment scores of M3 and M8 in three different age groups of different cerebral regions. Kruskal-Wallis test with Benjamini-Hochberg correction was used to determine statistical significance. The black circle and bar represent median and quartiles (25th and 75th percentile), respectively. *q < 0.05, **q < 0.01, ***q < 0.001. ACC, Anterior cingulate cortex; HIP, hippocampus; NAc, nucleus accumbens. (D) Violin plots of logFC values for genes of M3 and M8 between AD cases and controls in 7 cerebral regions. EC, entorhinal cortex; HIP, hippocampus; DLPFC, dorsolateral prefrontal cortex; PCG, postcentral gyrus; FP, frontal pole; STG, superior temporal gyrus; PHG, parahippocampal gyrus; IFG, inferior frontal gyrus. (E) PPI network of 345 DEGs with absolute logFC > 0.2 and q < 0.05 in at least 4 brain regions. The network was created by representing each gene as a node and connecting pairs of nodes with confidence >0.5. Node size is proportional to the degree. Hub genes with the highest degrees are labeled in black.
FIGURE 4
FIGURE 4
Expression change of M3 and M8 in AD at single-cell resolution. (A) Comparison of gene expression scores of M3 and M8 between AD cases and controls in different neuronal subtypes of the prefrontal cortex (PFC). Mann-Whitney test with Benjamini-Hochberg correction was used to determine statistical significance. The black circle and bar indicate median and quartiles (25th and 75th percentile), respectively. *q < 0.05, **q < 0.01, ***q < 0.001, ****q < 0.0001. (B) Differential expression analysis of hub genes between AD patients and controls in different neuronal subtypes. Blue and red colors indicate downregulation and upregulation respectively. Only genes with absolute LogFC > 0.14 are shown. *q < 0.05. Exc, excitatory neuron; Inh, inhibitory neuron.
FIGURE 5
FIGURE 5
Representative GSEA enrichment pathways of GHK-induced transcriptional responses. The pathways shown in the picture are citrate cycle (TCA cycle) (hsa00020); glutathione metabolism (hsa00480); biosynthesis of amino acids (hsa01230); and autophagy-animal (hsa04140).
FIGURE 6
FIGURE 6
The neuroprotective effect of tripeptide GHK against Aβ25–35-induced cytotoxicity in differentiated human SH-SY5Y cells. (A–C) Statistical data showing LDH release from cells treated with (A) different concentrations of Aβ25–35 for 24 h, (B) different concentration of GHK for 24 h, (C) different concentrations of GHK for 6 h before addition of Aβ25–35 (20 μM) for another 24 h. (D) mRNA expression level of 10 hub genes in cells of control group, Aβ25–35 group, Aβ25–35 + GHK group. Values represent mean ± SEM (n = 9) and are normalized to the control group (black column). ANOVA with Dunnet’s post-hoc test was used to determine statistical significance. **p < 0.01, ***p < 0.001, *⁣*⁣**p < 0.0001, compared to control group, #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001, compared to Aβ25–35 treatment group.
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References

    1. 2021 Alzheimer’s disease facts and figures (2021). Alzheimers Dement. J. Alzheimers Assoc. 17 327–406. 10.1002/alz.12328 - DOI - PubMed
    1. Agamah F. E., Mazandu G. K., Hassan R., Bope C. D., Thomford N. E., Ghansah A., et al. (2020). Computational/in silico methods in drug _target and lead prediction. Brief. Bioinform. 21 1663–1675. 10.1093/bib/bbz103 - DOI - PMC - PubMed
    1. Agrawal S. (2017). Alzheimer’s Disease: Genes. Mater Methods 7:2226. 10.13070/mm.en.7.2226 - DOI
    1. Ahmed M. R., Basha S. H., Gopinath D., Muthusamy R., Jayakumar R. (2005). Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes. JPNS 10 17–30. 10.1111/j.1085-9489.2005.10105.x - DOI - PubMed
    1. Alberghina M., Lupo G., La Spina G., Mangiameli A., Gulisano M., Sciotto D., et al. (1992). Cytoprotective effect of copper(II) complexes against ethanol-induced damage to rat gastric mucosa. J. Inorg. Biochem. 45 245–259. 10.1016/0162-0134(92)84013-d - DOI - PubMed

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