A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

Lee, Soo-Youn; Song, Min-Young; Kim, Dain; Park, Chaewon; Park, Da Kyeong; Kim, Dong Geun; Yoo, Jong Shin; Kim, Young Hye

doi:10.3389/fphar.2019.01653

Cited by 24 publications

(17 citation statements)

References 60 publications

(68 reference statements)

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“…The risk factors of development for AD diagnosis are important, of which age is dominant ( Currais et al, 2019 ). As the population ages, the prevalence of AD is increasing ( Lee et al, 2019 ). Studies have shown that for people over 60, the incidence doubles per 6.3 years.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Liu

Pan

2021

Front. Genet.

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BackgroundAs the most common neurodegenerative disease, Alzheimer’s disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.MethodsThe gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.ResultsThere was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.ConclusionA model based on immune cell infiltration might be used to forecast AD patients’ diagnosis, and it provided a new perspective for AD treatment targets.

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Section: Introductionmentioning

confidence: 99%

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Liu

Pan

2021

Front. Genet.

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“…Here, based on these molecular characteristics and an efficient and widely used computational drug-genomic method 23 – 25 , we identified multiple drugs that may have the potential to convert a noninflamed environment into an inflamed tumor environment (Fig. 6a ).…”

Section: Resultsmentioning

confidence: 99%

Multiomics characteristics of neurogenesis-related gene are dysregulated in tumor immune microenvironment

et al. 2021

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The success of immunotherapy was overshadowed by its low response rate, and the hot or cold tumor microenvironment was reported to be responsible for it. However, due to the lack of an appropriate method, it is still a huge challenge for researchers to understand the molecular differences between hot and cold tumor microenvironments. Further research is needed to gain deeper insight into the molecular characteristics of the hot/cold tumor microenvironment. A large-scale clinical cohort and single-cell RNA-seq technology were used to identify the molecular characteristics of inflamed or noninflamed tumors. With single-cell RNA sequencing technology, we provided a novel method to dissect the tumor microenvironment into a hot/cold tumor microenvironment to help us understand the molecular differences between hot and cold tumor microenvironments. Compared with cold tumors, hot tumors highly expressed B cell-related genes, such as MS4A1 and CXCR5, neurogenesis-related miRNA such as MIR650, and immune molecule-related lncRNA such as MIR155HG and LINC00426. In cold tumors, the expression of genes related to multiple biological processes, such as the neural system, was significantly upregulated, and methylome analysis indicated that the promoter methylation level of genes related to neurogenesis was significantly reduced. Finally, we investigated the pan-cancer prognostic value of the cold/hot microenvironment and performed pharmacogenomic analysis to predict potential drugs that may have the potential to convert the cold microenvironment into a hot microenvironment. Our study reveals the multiomics characteristics of cold/hot microenvironments. These molecular characteristics may contribute to the understanding of immune exclusion and the development of microenvironment-targeted therapy.

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“…This will allow a better prognostic classification of the patients and a better management of the probands and of their families, by the identification of the -at risk individuals. These genetic data, together with novel clues coming from other “omics” [ 90 , 91 , 92 ], will allow also the development of novel and even more personalized therapies for AD and FAD treatment.…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Molecular Bases of Familial Alzheimer’s Disease

D’Argenio

Sarnataro

2020

JPM

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Like several neurodegenerative disorders, such as Prion and Parkinson diseases, Alzheimer’s disease (AD) is characterized by spreading mechanism of aggregated proteins in the brain in a typical “prion-like” manner. Recent genetic studies have identified in four genes associated with inherited AD (amyloid precursor protein-APP, Presenilin-1, Presenilin-2 and Apolipoprotein E), rare mutations which cause dysregulation of APP processing and alterations of folding of the derived amyloid beta peptide (Aβ). Accumulation and aggregation of Aβ in the brain can trigger a series of intracellular events, including hyperphosphorylation of tau protein, leading to the pathological features of AD. However, mutations in these four genes account for a small of the total genetic risk for familial AD (FAD). Genome-wide association studies have recently led to the identification of additional AD candidate genes. Here, we review an update of well-established, highly penetrant FAD-causing genes with correlation to the protein misfolding pathway, and novel emerging candidate FAD genes, as well as inherited risk factors. Knowledge of these genes and of their correlated biochemical cascade will provide several potential targets for treatment of AD and aging-related disorders.

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A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

Cited by 24 publications

References 60 publications

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Multiomics characteristics of neurogenesis-related gene are dysregulated in tumor immune microenvironment

New Insights into the Molecular Bases of Familial Alzheimer’s Disease

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