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Alzheimer's disease AD is the most common form of senile dementia characterized by neuronal death, loss of synaptic function and atrophy in areas of the brain that affect cognitive functions and memory 1 , 2. The prevalence of AD is estimated to triple by , increasing significant economic and social burden on patients and society 3. Currently, cognitive testing and neuroimaging remain the gold standard for the diagnosis of AD 4 ; however, these clinical techniques are complicated and expensive 5. Thus, simple and convenient biomarkers are critically required to improve diagnosis of early stage AD 6. Screening for biomarkers in patients with AD is predominantly reported for cerebrospinal fluid, blood and other biological samples, such as urine, breath and saliva 7 , 8. Increasing evidence has demonstrated that detection of biomarkers in peripheral blood is minimally invasive, low-cost and easily applied for mass screening 9 , It has been reported that miRNAs are ideal biomarkers due to their stability in body fluids, and can be attributed to specific organs and pathologies in AD For example, Hara et al 13 demonstrated that hsa-miRp may be a serum biomarker that could correspond to pathological events occurring in the brain of patients with AD. Additionally, Jia and Liu 14 reported that downregulated hsa-miR serum may serve as a biomarker in AD, as demonstrated by quantitative PCR analysis of serum samples from 84 probable sporadic patients with AD and 62 healthy individuals in China. Currently, a number of studies have identified several miRNAs or mRNAs that are significantly differentially expressed DE in the blood from patients with AD compared with normal control samples, indicating their key functions in the pathogenesis of AD 13 , However, the comparability of these studies is particularly challenging due to their small sample size, as well as differences in their quantification methods and protocols. There is a need to combine the study results using a meta-analysis approach to improve the understanding of the molecular mechanisms underlying AD. Chen et al 15 analyzed nine representative miRNA datasets of AD samples, which originated from tissues, serum, extracellular or cerebrospinal fluid, and identified 13 key miRNAs associated with AD. However, a detailed map of specific biomarkers in the blood of patients with AD is still lacking. The present study systematically analyzed 15 representative miRNA and mRNA datasets of the blood from patients with AD using a series of bioinformatics methods. The present study collected 12 representative miRNA and three mRNA expression profiles of blood samples from patients with AD and normal control samples. All datasets contained at least three AD samples and had age-matched normal control samples in each group. Among the 12 miRNA expression datasets, seven focused on serum 9 , 10 , 13 , 14 , 18 — 20 , three on plasma 21 — 23 , one on both serum and plasma 24 , and one focused on whole blood The three mRNA expression datasets all focused on whole blood 5. Detailed information of these datasets are presented in Table I. Subsequently, the Limma package in R language version 3. In the case where multiple probes corresponded to the same gene, the probe with the maximal value was selected as the expression of that particular gene. Euclidean distance was selected as a measure of distance between the samples. The hub nodes in the network were nodes with high scores of network topology property indictors, which were analyzed using CytoNCA version 2. In general, a high score of network topology property indictors indicates important roles in the network. Gene Ontology GO analysis, which organizes genes into hierarchical categories and determines the gene regulatory network on the basis of biological process BP , molecular function MF and cellular component CC , was applied to analyze the functions of genes. Kyoto Encyclopedia of Genes and Genomes KEGG pathway analysis was used to determine which signaling pathways the genes were enriched in. The workflow of the present study is presented in Fig. The present study downloaded 12 separate miRNA expression profiling datasets of blood samples from patients with AD and normal control samples. Detailed information on sample size, blood component and experimentally supported DEmiRNAs were manually extracted from the references of the datasets Table I. Among these, mRNAs were upregulated and 1, were downregulated in patients with AD compared with normal control samples. Heatmap of cluster analysis of differentially expressed mRNAs between patients with AD and normal control samples. Rows represent genes and columns represent samples. The values indicate the expression levels of the genes. Red represents normal control blood samples and blue represents blood samples from patients with AD. AD, Alzheimer's disease. Of these, hsa-miR-9 had the highest connectivity and was demonstrated to negatively interact with 14 target mRNAs. A high score of network topology property indictors suggests a notable role in the network. According to the rankings of network topology property indictors, including degree centrality, betweenness centrality and closeness centrality, the top five nodes of the downregulated miRNAs-mRNA network, which consisted of nodes and edges, are listed in Table II. A total of five miRNAs, including hsa-miR, hsa-miRb, hsa-miRa, hsa-miRp and hsa-miRb-5p were among the top nodes for all topology property indictors, suggesting their critical roles in the pathogenesis of AD. Red rectangles represent the target mRNAs that are enriched in the neurotrophin signaling pathway. Increasing evidence has demonstrated that identifying biomarkers using meta-analysis is helpful to the diagnosis and targeted therapy of patients with AD at an early stage 15 , Conversely, the present study focused on datasets from the blood. Although different strategies were used, some of the key miRNAs identified in the present study were in agreement with previous studies, for example, hsa-miRb, hsa-miRb and hsa-miR were also identified by Chen et al These protein-coding genes were significantly upregulated in patients with AD and enriched in the AD-associated pathway in the present study. Dong et al 19 reported that hsa-miR was markedly decreased in the serum of patients with AD compared with controls, while screening the expression profile of serum miRNAs by Solexa sequencing. In addition, it was demonstrated that the panel of hsa-miR, along with hsa-miR and miRa, may be used to discriminate AD from vascular dementia. Takashima et al 34 reported that hsa-miR may be a potential prognostic biomarker in primary central nervous system lymphoma. GAPDH is a family of abundantly expressed oxidoreductases that are known for their role in glucose metabolism Consistent with previous findings, the results of the present study demonstrated that hsa-miRb was significantly downregulated in patients with AD compared with the normal control samples, whereas the corresponding mRNAs were upregulated in patients with AD 25 , The neurotrophin signaling pathway is activated by neurotrophins through binding to the tyrosine protein kinase receptor family, which results in a series of neuronal functions, such as axonal growth, cell survival, cell differentiation, dendritic arborization, synapse formation, plasticity and axonal guidance 40 , The insulin signaling pathway, which is the main signal transduction pathway in insulin physiological function, serves a vital role in the metabolism, nerve protection and regulation of cognitive dysfunction Increasing evidence has demonstrated that the symptoms of patients with AD are consistently accompanied with a disordered insulin signaling pathway or other symptoms, suggesting that the insulin signaling pathway may be closely associated with the pathogenesis of AD In conclusion, availably representative miRNA and mRNA expression profiling datasets of the blood from patients with AD were collected and subjected to comprehensive analysis though a series of bioinformatics methods in the present study. However, further experimental studies testing these results would be desirable. Taken together, the results of the present study provided a valuable resource for depicting the complexity of AD, and may contribute to the development of diagnostic biomarkers and therapeutic targets for AD. All authors read and approved the final manuscript. J Alzheimers Dis. Alzheimers Dement. Mol Neurobiol. Genome Biol. Mol Psychiatry. J Neurol Sci. Mol Med Rep. Acta Neuropathol Commun. Cell Biochem Funct. J Gene Med. Med Pharm Rep. Nucl Acids Res. Dis Markers. Exp Ther Med. PLoS One. J Clin Psychiatry. Int J Mol Med. Nucleic Acids Res. J Biomed Inform. Nat Genet. View Article : Google Scholar. Nat Protoc. Neurobiol Aging. Med Sci Monit. Acta Neurol Scand. Int J Mol Sci. University of Wuzburg, Faculty of Science. J Pathol. August Volume 22 Issue 2. Sign up for eToc alerts. You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy. I agree. Home Submit Manuscript My Account. Advanced Search. Register Login. Molecular Medicine Reports. This article is mentioned in:. Introduction Alzheimer's disease AD is the most common form of senile dementia characterized by neuronal death, loss of synaptic function and atrophy in areas of the brain that affect cognitive functions and memory 1 , 2. Table I. Figure 1. Figure 2. Figure 3. Table II. Table III. Figure 4. Table IV. Related Articles. This site uses cookies. Spandidos Publications style. Mol Med Rep , Wang, Z. Molecular Medicine Reports, 22, Molecular Medicine Reports Molecular Medicine Reports 22, no. Tan et al Galimberti et al Dong et al Zhu et al Jia et al Hara et al Kumar et al Kiko et al Wang et al Liu et al Serum, plasma. Leidinger et al Whole blood. Biological process. Regulation of transcription, DNA-dependent. Apoptotic process. Inflammatory response. Signal transduction. Protein phosphorylation. Regulation of cell shape. Cell proliferation. Interspecies interaction between organisms. Molecular function. Metal ion binding. DNA binding. Zinc ion binding. Sequence-specific DNA binding transcription factor activity. Transferase activity. ATP binding. Protein binding. Nucleotide binding. Sequence-specific DNA binding. Kinase activity. Cellular component. Nuclear speck. Integral to membrane. Soluble fraction. Golgi apparatus. Endoplasmic reticulum. Neurotrophin signaling pathway. Insulin signaling pathway. MAPK signaling pathway. Alzheimer's disease. Huntington's disease. Wnt signaling pathway. Notch signaling pathway.
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Integrated analysis of miRNA and mRNA expression in the blood of patients with Alzheimer's disease
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Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood–Brain Barrier Damage
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