Neurobiology and Biomarkers of Brain Aging: miRNA in Alzheimer's and Depression
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This document summarizes a presentation on microRNAs in Alzheimer's disease and depression. It discusses the characteristics of microRNAs, how they can serve as biomarkers for disease detection and monitoring treatment response. Specific microRNAs have been associated with Alzheimer's and depression. The presentation analyzes studies identifying microRNAs differently expressed in Alzheimer's and depression. A few microRNAs are common to both conditions. Gene therapy techniques can be used to up-regulate or down-regulate microRNA levels as a potential treatment approach.
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Neurobiology and Biomarkers of Brain Aging: miRNA in Alzheimer's and Depression
- 1. I International Symposium: Neurobiology and Biomarkers of Brain Aging microRNA in Alzheimer’s disease and Depression Ana Paula Mendes Silva PhD Student Federal University of Minas Gerais/UFMG
- 2. Biomarkers miRNA Characteristics Advantages and limitations Major depressive disorder Alzheimer’s disease Gene therapy
- 4. CChhaarraacctteerriissttiiccss • Non-coding RNA microRNAs mediate translational repression or mRNA degradation Post-transcriptional regulators of miRNA gene expression 18 to 22-nucleotides-long http://mcb.berkeley.edu/labs/he/Research.htm
- 5. CChhaarraacctteerriissttiiccss • Horizontal transfer of miRNAs by secreted extracellular vesicles -> intercellular communication http://circres.ahajournals.org/content/110/3/483.abstract
- 6. CChhaarraacctteerriissttiiccss • A single miRNAs can target multiple mRNAs ARID1A FAM7A3 BHLHB9 SLC10A2 PKN2 COPG hsa-miR-664 ZNF423 GPHN IRF2 STRAP ARID1B CPEB4 KCMF1 KLF12 AHCTF1P MDGA2 ADCYAP1 FAM7A1 RSBN1 FRMPD4 AHCTF1 CT47A9 TTC33 SMYD1 ZMYND11 RBM26
- 7. CChhaarraacctteerriissttiiccss • Multiple miRNAs can target a single mRNA BDNF hsa-miR-1 hsa-miR-206 hsa-miR-613 hsa-miR-374b hsa-miR-495 hsa-miR-374a hsa-miR-10a hsa-miR-195 hsa-miR-216b hsa-miR-30a hsa-miR-122 hsa-miR-30e
- 8. BBiioommaarrkkeerr • A biomarker is an indicator of physiological, biochemical, or anatomic parameter BBiioollooggiiccaall PPrroocceesssseess PPaatthhoollooggiiccaall PPrroocceesssseess TThheerraappeeuuttiicc IInntteerrvveennttiioonn
- 9. BBiioommaarrkkeerr • miRNAs can be detected in serum, plasma, urine, and other biological fluids BBooddyy fflluuiiddss http://www.mirnabodymap.org/
- 10. AAddvvaannttaaggeess • Horizontal transfer • Mature miRNAs are small • Stable molecules • Resistant to RNA degradation • Highly conserved among species
- 11. AAddvvaannttaaggeess • Differentiate pathological phenotypes • Provide global disease profiling • Customized treatment: – Rational drug selection – Monitoring response to therapy • Alows risk stratification
- 12. AAddvvaannttaaggeess • Noninvasive biomarkers • Positive impact in patient comfort • Can lead to early diagnosis • Might enable patients to get on treatments earlier, preventing the devastanting effects of the disease
- 13. LLiimmiittaattiioonnss • It’s difficult to measure each miRNA contribuition to the disease • The presence of miRNAs in collected fluids does not directly indicate the inhibition of the translation process • Although a single miRNA can be related with multiple pathologies it does not necessarily mean that all the pathologies will develop • Cost of miRNA sequencing
- 14. MMeettaa--aannaallyyssiiss Identification Records identified through Web of Science Included Eligibility Screening Records identified through PubMed Records identified through SCOPUS 416 AD Records after duplicates removed 176 D Records screened Records excluded, because they are reviews, book chapters, meeting abstracts, descriptive articles and protocoll papers Full-text articles accessed for eligibility Full-text articles excluded, miRNAs specific cell, animal models and the blood of patients under the use of any medication 6 AD Studies included in the analysis 3 D http://www.prisma-statement.org/
- 15. AAllzzhheeiimmeerr’’ss ddiisseeaassee • The words used to identify the miRNAs related to Alzheimer’s were: Alzheimer’s disease and miRNA. • Identified 77 miRNAs differently expressed
- 21. MMaajjoorr ddeepprreessssiivvee ddiissoorrddeerr • The words used to identify the miRNAs related to depression were: (Major depressive disorder OR depressive disorder OR depression) and miRNA. • Identified 32 miRNAs differently expressed
- 24. MiRNAs common to AAllzzhheeiimmeerr’’ss ddiisseeaassee aanndd ddeepprreessssiioonn hsa-miR-26b hsa-miR-664 hsa-let-7d hsa-let-7g 5418 115555 ggeenneess 5544 8089 hsa-miR-191 hsa-let-7f hsa-miR-30d hsa-miR-361-5p 5467 7467 6114 2015 5616
- 25. NNeettwwoorrkk
- 26. GGeennee tthheerraappyy • Up-regulated – AntagomiRs are used to decrease the levels of specific miRNA • Down-regulated – Synthetic RNAs or siRNAs are used to increase the levels
- 27. GGeennee tthheerraappyy miRNAs Regulation FoldChange hsa-miR-766-3p Down-regulated 9,54 hsa-miR-26b-5p Down-regulated 8,58 hsa-miR-340-5p Up-regulated 7,61 hsa-miR-6509-5p Up-regulated 7,43 cel-miR-39 Baseline (endogenous) _____________ Genome-wide sérum microRNA expression. Profiling identifies sérum biomarkers for Alzheimer’s disease. Tan, L.; Yu,J.T.; Tan, M.S.; Liu, Q.Y.; Wang, H.F.; Zhang, W.; Jiang, T. and Tan.L. Journal of Alzheimer’s disease 40 (2014) 1017-1027.
- 28. TThhaannkk YYoouu ffoorr yyoouurr aatteennttiioonn!! e-mail: apmendes@ufmg.br
Notes de l'éditeur
- Good Afternoon. My name is Ana Paula, I am a phD student in Molecular Medicine at the Federal University of Minas Gerais. First of all, I’d like to say it’s na honor to be invited to presente and discuss the work i have been developing. It’s na excelente opportunity for us to exchange and work on some of our doubts. The objetive of my work is to identify the miRNAs that assist in early diagnosis of Alzheimer’s disease and major depressive disorder.
- In this way, It’s importante for us to know about characteristics of this molecule. Why is it considered a biomarker? What are the advantages and limitations of using miRNAs? Which one of them, among those already found in literature, are related to Alzheimer’s disease and depression. And what is the future perspective of miRNas gene therapy?
- In order to have na overview of the process involving the study of biomarkers, as seen in miRNAs, we need to understand their biogenesis mechanisms. Where in the body can they be foud? What are the extraction methodologies used? Which tools are available and how should they be used to quantify the miRNAs expression? What are the clinical applications of this biomarker in prognosis, diagnosis and customized gene therapy?
- The miRNas are included in the non-coding RNA Family. Each molecule is 18 to 22 nucleotides-long. Their basic function is to regulate mRNA repression and degradation throughout the translation process. Repression works as a physical mechanism to prevent association between rRNA and mRNA. The complete degradation happens after the complex RISC associates itself with the mRNA. Thus, the miRNAs are post-transcriptional regulators of gene expression.
- The miRNAs are produced inside the cellular nucleus. They may act on the cytoplasm of the cell that produces them. They may be transferred horizontally by exosome, microvesicles, associated to HDL or proteins such as Argonauta.
- One of the most important characteristics of miRNAs is that a single miRNAs can target multiple mRNAs. A single miRNA can interfere in a variety of physiological mechanism in gene expression. Characterizing a large amount of regulation mechanisms, involving multiple genes. As an example we have the miRNA-130b which is involved in the regulation of 116 genes and we also have the let-7d which is involved in the regulation of 126 genes. In adition, different miRNAs can have the same target mRNA, which makes the global study of the regulation mechanism in a single gene even more complex. Differently from when we study the relationship between a mRNA and its gene. Therefore, the miRNAs could indicate the regulation genes, possibly associated with diseases such as Alzheimer’s and depression. a single mRNA can also be targeted by multiple miRNAs
- One of the most important characteristics of miRNAs is that a single miRNAs can target multiple mRNAs. A single miRNA can interfere in a variety of physiological mechanism in gene expression. Characterizing a large amount of regulation mechanisms, involving multiple genes. As an example we have the miRNA-130b which is involved in the regulation of 116 genes and we also have the let-7d which is involved in the regulation of 126 genes. In adition, different miRNAs can have the same target mRNA, which makes the global study of the regulation mechanism in a single gene even more complex. Differently from when we study the relationship between a mRNA and its gene. Therefore, the miRNAs could indicate the regulation genes, possibly associated with diseases such as Alzheimer’s and depression. a single mRNA can also be targeted by multiple miRNAs
- A biomarker is an indicator of physiological, biochemical, or anatomic parameter. And that can objectively be measured in normal biologic processes, pathological processes, or responses to a therapeutic intervention. The extraction and quantifying process of biomarkers should be easy and guaranteed. Thus, the employ of miRNAs as a biomarker of these diseases.
- miRNAs can be easily detected and extract from serum, plasma, urine, and other biological fluids. And according to literature, they may be associated with many diseases such as cancer and neurodegenerative processes.
- Considering all of characteristics discussed, we are able to list the advantages and limitations of using miRNAs to identify diseases. The most relevant advantages when comparing miRNAs to proteins and mRNAs are: It is easiers to transfer miRNAs horizontally, which alows the gathering of miRNAs from cells or fluid that are not directly related to a pathology, avoiding the necessity of biopsis. They are small molecules miRNAs have more stability, since they are transported inside microvesicles or associated with proteins. Thus, they are more resistant to RNA degradation. Furthermore their molecules have a high rate of conservation among species, making them easier to study, even in animal models.
- They assist in defferentiating the methabolic process of diseases thathave the same pathological phenotype and that are not necessarily regulated by the same miRNAs or genes. Once we identify the miRNAs involved in the pathology, we may characterize the global regulation profile of the disease. It alows a customized treatment, based on the individual profile of the pathology, alowing the selection of specific drugs and the monitoring of the therapy results. By doing this they diminsh the necessity of biopsis made from affected tissue.
- It’s a non-invasive biomarker for the diagnosis of many neurodegenerative diseases. It contributes positively for the wellbeing of the patient. The early diagnosis is possible through the identification of the target miRNAs in body fluids. Thus, there is no need to wait for the disease to evolve before satrting treatment. These biomarkers prevent the worst effects of the disease, effects such as massive cell death.
- It’s difficult to measured the individual miRNA contribution in the development of the disease. Because there are many genes involved in the pathology and many miRNAs regulate a single gene. The presence of miRNAs in collected fluid does not directly indicate the inhibition of the translation process. Although a single miRNA can be related with multiple pathologies it does not necessarily mean that all the pathologies will develop. The cost of miRNA’s sequencing is still too high to be done in laboratorial scale.
- In order to understand the regulation mechanisms of gene expression in Alzheimer’s disease and depression we performed a meta-analysis following the parameters of prisma guidelines. We aimed to identify the miRNAs, which have already been described in literature, that are involved in both pathologies,. Initially we used specific key – words to identify records in databases such as Web of Science, Pubmed and SCOPUS. Finally, we collected only the miRNAs data with p-value under 5% and fold change greater than 1.5.
- The words used to identify the miRNAs related to Alzheimer’s were: Alzheimer’s disease and miRNA. Through the identification of six studies we found 77 miRNAs express themselves differently in elder patients with Alzheimer than when compared to normal patients. Which are listed in the chart below.
- The words used to identify the miRNAs related to depression were: (Major depressive disorder OR depressive disorder OR depression) and miRNA. We identified of 3 studies and found 32 miRNAs expressed differently in elder patients with depression when compared to normal patients. They are related in the chart below.
- Individually, eachone acts upon the gene expression of 2000 to 8000 genes. Being that of all of these genes, 155 of them are regulated by 8 miRNAs in common.
- The network between these 155 genes shows us how complex the gene regulation is.
- Antagomirs relacionados aos miRNAs -> down-regulated Utilização de miRNas -> up-regulated
- I hope i was able to show you how my work is importante and i hope to be able to answer to the following questions