Related studies have suggested that MDD and AD mutually contribute to each other's risk of occurrence(Berger et al., 2020). It has been reported that patients with MDD suffer from an elevated prevalence of AD, who in turn commonly suffer from symptoms of depression(Lutz et al., 2020). Nevertheless, to date, there are no investigated potent drugs to address AD, while approximately one-third of depressed individuals manifest resistance to the treatment. Since the biological association between MDD and AD remains elusive, the revelation of this association might well initiate novel preventive or therapeutic options for MDD and AD, thereby optimizing health care for this group of patients. The present study analyzed the common DEGs in the peripheral blood of MDD and AD patients from the aspect of biological, in an attempt to present scientific grounds for the early diagnosis and intervention of these two disorders.
There were 31 common DEGs identified and these DEGs were analyzed by a comprehensive bioinformatics approach. The outcomes of GO analysis, which consisted of BP, MF and CC suggested that majority of these common DEGs were enriched in cytoplasmic translation, fructose-2,6-bisphosphate 2-phosphatase activity, tertiary granule lumen. Additionally, the analysis of pathway enrichment indicated that these common DEGs were remarkably enriched in the Cytoplasmic Ribosomal Proteins, Ribosome, Viral mRNA Translation, TSP-1 Induced Apoptosis in Microvascular Endothelial Cell pathways. These functional and pathway enrichments of common DEGs provided additional insights into the underlying molecular mechanisms concerning the onset and progression of MDD and AD.
By constructing the PPI network, we identified 10 hub genes, including RPS3A, RPS15A, RPL9, NDUFA4, RPS17, MMP9, CD3D, GZMA, S100A12 and KLRB1. By validating these 10 hub genes, we have discovered that RPS3A, RPS15A, RPL9, NDUFA4, RPS17, CD3D, GZMA, S100A12 and KLRB are statistically significant differences in the expression of the dataset of GSE63061. RPS3A(Tao et al., 2020)was determined to be potential biomarker for the pathogenesis of AD, and this gene represents one of the crucial genes connecting Mild Cognitive Impairment (MCI) and AD. RPS15A, as a ribosomal protein, is deeply conserved in various organisms ranging from yeast to human. It was discovered in numerous studies(Kong et al., 2020; Xu et al., 2021) as a major contributor to the growth of cancer cells. Variants of RPL9 can impair cellular metabolism as well as ribosome function to varying degrees and are closely associated with tumorigenesis and progression(Lezzerini et al., 2020). NDUFA4, one of the subunits of cytochrome c oxidase (CIV), serves an essential role in the function and biogenesis of CIV, and it was identified that NDUFA4 mutations underlie the dysfunction of CIV subunits associated with human neurological disorders(Pitceathly et al., 2013). Presently, mitochondrial dysfunction is a key feature of neurodegenerative diseases, including AD, and has been investigated in AD(Adav et al., 2019). Mutations in RPS17 are intimately associated with Diamond-Blackfan anemia, and studies have identified RPS17 as a potential biomarker for the development of AD(Wang et al., 2021). Immune and inflammatory responses are closely related to the pathophysiological mechanisms of MDD and AD. CD3D has been shown to be a reliable marker of MDD and positively correlates with T-cell CD8(Ning et al., 2022). GZMA, a pyroptosis-related genes, was found to predict and diagnose the immune profile of MDD(Deng et al., 2022). Abundantly expressed in neutrophils during acute inflammation and associated with immune regulation, S100A12 is a valuable biomarker during inflammation and has been found to have a potential role in the pathogenesis of AD(Shepherd et al., 2006). Zhao et al.(Zhao et al., 2021) applied the machine learning approach to identify KLRB1 as a diagnostic marker for MDD. Consequently, among these 10 hub gene, except for MMP9, the other 9 genes may be critical novel factors affecting the development of MDD and AD, and may be potential novel diagnostic and therapeutic targets for MDD and AD.
TFs and miRNAs exert critical regulatory roles in the expression of genes, and both are potential biomarkers for complex diseases. The characterization of TFs and miRNAs that regulate target genes is essential for the better comprehension of the mechanisms of disease development and the identification of potential biomarkers. The present study identified that the top five TFs that most intimately regulated the common DEGs were GTF2E2, FOXJ2, CREB3L1, TFDP1 and SAP30. General transcription factor IIE subunit beta (GTF2E2), as part of the RNA polymerase II transcription initiation complex, is essential for both physiological and pathological functions of the organism. Its role in the growth and apoptosis of tumor cells has been investigated(Y. Zhang et al., 2022), but it remains ambiguous in the development and progression of MDD and AD. FOXJ2(Gómez-Ferrería & Rey-Campos, 2003), a forkhead transcriptional activator, with an early expression in embryonic development and a wide distribution in adulthood, it might play an essential role in the development and survival of neurons, but no studies have yet found its role in MDD and AD. CREB3L1(Mellor et al., 2013), a novel suppressor of tumor metastasis, has been investigated to suppress the expression of genes that regulate metastasis, invasion and angiogenesis, but its role in MDD and AD remains unclear. TFDP1(Yasui et al., 2002), with a significant role in the regulation of the cell cycle, which dominantly regulates the transactivation of a wide range of genes involved in the progression of the cell cycle from G1 to S phase, is a novel biomarker for various tumors, but no studies have yet demonstrated its role in the progression of MDD and AD. By binding to the transcriptional repressor mSin3, SAP30 can mediate transcriptional repression via histone deacetylases(Y. Zhang et al., 1998). Whereas histone acetylation plays a key role in regulating eukaryotic gene expression, SAP30 has an essential role in the biological function of eukaryotes, while its role in MDD and AD remains unknown. Therefore, these five TFs all have the possibility to become potential novel biomarkers for the early diagnosis and treatment of MDD and AD.
Moreover, the top five miRNAs are mir-16-5p, mir-1-3p, mir-124-3p, mir-7-5p and mir-146a-5p. It has been suggested that the accumulated β-amyloid (Aβ) in brain is a major contributor to the death of neuronal cells in AD. mir-16-5p can be upregulated by deposited Aβ in AD and induces neuronal injury and apoptosis of neuronal cells by directly targeting and repressing the expression of related genes(Kim et al., 2020). Furthermore, mir-16-5p has been identified as a potential marker of MDD(Rasheed et al., 2022). mir-1-3p played an important role in the regulation of tumor associated genes, and no studies have yet identified its role in the regulation of AD and MDD related genes. Bhaskar Roy et al.(Roy et al., 2017) have identified dysregulation of mir-124-3p in serum of MDD without antidepressants, and their study have demonstrated the potential contribution of mir-124-3p in the pathophysiology of MDD and have suggested that it may serve as a potential biomarker of MDD. And it has been identified as a potential marker of AD(Rahman et al., 2019). Studies have found increased expression of mir-7-5p in AD(La Rosa et al., 2021), which may serve as a potential biomarker for AD diagnosis, and no studies have yet found changes in its expression in MDD. It was found that upregulation of mir-146a-5p promoted oxidative stress and cellular scorching in AD hippocampal neurons by targeting TIGAR and could trigger oxidative stress via MAPK signaling to exacerbate cognitive impairment and pathological changes of AD(Lei et al., 2021). It is also a marker of antidepressant response in MDD patients and regulates genes of the MAPK/Wnt system(Lopez et al., 2017). Overall, mir-1-3p and mir-7-5p have the possibility to be novel diagnostic and therapeutic targets of MDD and AD.
Through the analysis of protein-chemical associations, we identified that Aflatoxin B, Benzo(a)pyrene, Estradiol, Valproic Acid and Nickel interacted most intimately with common DEGs. It has been demonstrated that prolonged exposure to Aflatoxin B leads to pathophysiological changes in the body in a duration-dependent manner, and that these changes are associated with neurodegeneration, particularly AD(Alsayyah et al., 2019). Benzo(a)pyrene presents subchronic neurotoxicity and can lead to mitochondrial dysfunction and neuronal death, resulting in effects on MDD and AD(Ji et al., 2016). Studies have found that Estradiol could reduce the risk and delay the progression of AD, and might also contribute to neuroprotective effects by promoting recovery from neurological damage. Furthermore, Estradiol also exerts an essential role in the regulation of gene expression of serotonin neurotransmission associated with depression(Hernández-Hernández et al., 2019). Valproic acid, a commonly accepted antiepileptic and mood stabilizer, plays a neuroprotective role related to AD and it can be utilized to treat agitation or restlessness in patients with MDD(Vigo & Baldessarini, 2009). The deposition of tau aggregates in the brain is a pathologic trait of neurodegenerative diseases, including AD, and nickel was investigated to exert its neuroprotective effect by preventing aggregation through the induction of tau degradation(Gorantla et al., 2020). As Estradiol, Valproic Acid and Nickel possess neuroprotective properties, they are potential chemicals that can be utilized for the treatment of MDD and AD.
Through the analysis of gene-drug interactions, we identified that aspirin, medroxyprogesterone acetate, p-Phenylenediamine, COBALT and sodium dodecyl sulfate interacted most intimately with common DEGs. At present, aspirin has been investigated for the treatment of MDD and AD, and it can slow down the cognitive decline of patients with neuroprotective effects, but further clinical studies are required for its further application(Weng et al., 2021). Hormone replacement therapy has been adopted widely in the treatment of AD. Medroxyprogesterone Acetate, a progestin, can facilitate changes in circulating levels of matrix metalloproteinases (MMPs), and dysregulation of MMPs is associated with the pathological mechanisms of AD(Porter et al., 2020). However, whether it can be utilized in the treatment of MDD and AD is still controversial. It was discovered that p-Phenylenediamine could alleviate cognitive impairment, reduce the inflammatory response of nerves, and promote the clearance of Aβ in the brain, and that the drug has the potential to treat AD-related neurodegenerative pathologies(Park et al., 2019). Tau is among the biomarkers of AD, and studies have identified cobalt-based metal complexes which can be applied to inhibit the aggregation of Tau and possess neuroprotective effects, with the potential to be employed in metallotherapies for MDD and AD(Gorantla et al., 2019). Sodium dodecyl sulfate exhibits a micro-irritant effect on the skin and is primarily employed in gel electrophoresis; so far no studies have identified its usefulness in the treatment of MDD and AD. Consequently, aspirin, medroxyprogesterone acetate, p-Phenylenediamine, COBALT might be prospering for the treatment of MDD and AD.
Moreover, 53 potentially effective drugs for the treatment of patients with MDD and AD were identified through DGIdb. For these 53 drugs, there were 12 gene targets, and these 12 genes included 5 hub genes that we identified, namely NDUFA4, CD3D, GZMA, S100A12, and MMP9. The present study focused on the drugs that interacted with these 5 hub genes with the highest intensity. These five drugs were ME-344 targeting NDUFA4, MUROMONAB-CD3 targeting CD3D, CYCLOSPORINE targeting GZMA, ATOGEPANT targeting S100A12, and ANDECALIXIMAB targeting MMP9. ME-344(L. Zhang et al., 2019), a novel isoflavone exhibiting an exceptional cytotoxic profile, has been clinically tested for its cancer therapeutic potential, and its anticancer properties are primarily mediated by destabilizing the oxidation-reduction process and interfering with mitochondrial function. At present, the drug has been applied in the treatment of cancer and leukemia, but its application in the treatment of MDD and AD still requires further research. MUROMONAB-CD3(Todd & Brogden, 1989), the first monoclonal antibody that can be applied in human therapy, it blocks the functions of all cytotoxic T cells and is a remarkably powerful immunosuppressive agent that can be employed in the treatment of type I diabetes, as well as in the prevention and treatment of rejection of acute grafts. There are no studies that have identified its role in the treatment of MDD and AD. CYCLOSPORINE(Russell et al., 1992) is also an efficient agent for immunosuppression, which primarily suppresses the generation of cytokines that regulate the activation of T cells, especially IL-2, and can be employed in the treatment of transplant rejection and autoimmune diseases. However, its role in the treatment of MDD and AD has not yet been identified. ATOGEPANT(Goadsby et al., 2020) is a receptor antagonist of calcitonin gene-related peptide and is currently used primarily for the prevention and treatment of migraine. ANDECALIXIMAB(Shah et al., 2018), which targets the MMP9 gene, is a monoclonal antibody with selective and high affinity for inflammatory and tumorigenic diseases of the digestive system. By constructing a downstream network of these 12 drug target genes, the relationship between proteins and chemicals can be further discovered. This will provide further insight into the relationship of drugs to these proteins.
Nevertheless, there are still several limitations of our current study. Firstly, the number of subjects in the two datasets we selected for study is relatively small and further analysis should be performed by expanding the sample size or integrating more datasets so that our results can be extrapolated to a larger population. Secondly, bioinformatics approaches were employed to analyze and identify potential biomarkers, and the hub genes, TFs and miRNAs obtained in this study still need to be validated by experimental studies. Finally, the potential therapeutic agents identified by the bioinformatics approaches in this study also need further experiments to verify their applicability to the clinical treatment of MDD and AD.