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Translational Neurodegeneration

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Open Access 01-12-2016 | Research

miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer’s disease and other types of dementia – an exploratory study

Authors: Sofie Sølvsten Sørensen, Ann-Britt Nygaard, Thomas Christensen

Published in: Translational Neurodegeneration | Issue 1/2016

Abstract

Background

MicroRNAs (miRNAs) are small non-coding RNA molecules that function as posttranscriptional regulators of gene expression. Measurements of miRNAs in cerebrospinal fluid (CSF) and blood have just started gaining attention as a novel diagnostic tool for various neurological conditions. The purpose of this exploratory investigation was to analyze the expression of miRNAs in CSF and blood of patients with Alzheimer’s disease (AD) and other neurodegenerative disorders in order to identify potential miRNA biomarker candidates able to separate AD from other types of dementia.

Methods

CSF was collected by lumbar puncture performed on 10 patients diagnosed with AD and 10 patients diagnosed with either vascular dementia, frontotemporal dementia or dementia with Lewy bodies. Blood samples were taken immediately after. Total RNA was extracted from cell free fractions of CSF and plasma, and a screening for 372 known miRNA sequences was carried out by real time quantitative polymerase chain reactions (miRCURY LNA™ Universal RT miRNA PCR, Polyadenylation and cDNA synthesis kit, Exiqon).

Results

Fifty-two miRNAs were detected in CSF in at least nine out of ten patients in both groups. Among these, two miRNAs (let-7i-5p and miR-15a-5p) were found significantly up-regulated and one miRNA (miR-29c-3p) was found significantly down-regulated in patients with AD compared to controls. One hundred and sixty-eight miRNAs were frequently detected in the blood, among which miR-590-5p and miR-142-5p were significantly up-regulated and miR-194-5p was significantly down-regulated in AD patients compared to controls.

Conclusions

Detection of miRNA expression profiles in blood and in particular CSF of patients diagnosed with different types of dementia is feasible and it seems that several expressional differences between AD and other dementia types do exist when measured in a clinically relevant setup. In this explorative pilot study, the deregulated miRNAs in CSF of AD patients may be associated with relevant target genes related to AD pathology, including APP and BACE1, which suggests that miRNAs are interesting candidates for AD biomarkers in the future.

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Qiu C, Fratiglioni L. Epidemiology of Alzheimer’s disease. In: Waldemar G, Burns A, editors. Alzheimer’s Disease. Oxford: Oxford Neuropsyciatric Library; 2009. p. 17–27.

Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63–75.CrossRefPubMed

Wimo A, Jonsson L, Winblad B. An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Disord. 2006;21:175–81.CrossRefPubMed

LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci. 2007;8:499–509.CrossRefPubMed

Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8:663–72.CrossRefPubMed

Aliev G, Palacios HH, Walrafen B, Lipsitt AE, Obrenovich ME, Morales L. Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. Int J Biochem Cell Biol. 2009;41:1989–2004.CrossRefPubMed

Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy S a, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.

Rosa MI, Perucchi J, Medeiros LR, et al. Accuracy of cerebrospinal fluid Aβ(1–42) for Alzheimer’s disease diagnosis: a systematatic review and metaanalysis. J Alzheimers Dis. 2014;40:443–54.PubMed

Van Harten AC, Kester MI, Visser PJ, Blankenstein MA, Pijnenburg YAL, Van Der Flier WM, Scheltens P. Tau and p-tau as CSF biomarkers in dementia: A meta-analysis. Clin Chem Lab Med. 2011;49:353–66.

10.

Wang W-X, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008;28:1213–23.

11.

Lei X, Lei L, Zhang Z, Zhang Z, Cheng Y. Downregulated miR-29c correlates with increased BACE1 expression in sporadic Alzheimer’ s disease. Int J Clin Exp Pathol. 2015;8:1565–74.PubMedPubMedCentral

12.

Nelson PT, Wang W-X. MiR-107 is reduced in Alzheimer’s disease brain neocortex: validation study. J Alzheimers Dis. 2010;21:75–9.PubMedPubMedCentral

13.

Bekris LM, Lutz F, Montine TJ, Yu CE, Tsuang D, Peskind ER, Leverenz JB. MicroRNA in Alzheimer’s disease: an exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers. 2013;18:455–66.

14.

Wang W-X, Huang Q, Hu Y, Stromberg AJ, Nelson PT. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol. 2011;121:193–205.CrossRefPubMedPubMedCentral

15.

Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008;105:6415–20.

16.

Lukiw WJ. Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport. 2007;18:297–300.CrossRefPubMed

17.

Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett. 2009;459:100–4.CrossRefPubMed

18.

Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C, Prinjha RK, Richardson JC. Identification of miRNA Changes in Alzheimer’ s Disease Brain and CSF Yields Putative Biomarkers and Insights into Disease Pathways. J Alzheimer’s Dis. 2008;14:27–41.

19.

Coolen M, Katz S, Bally-Cuif L. miR-9: a versatile regulator of neurogenesis. Front Cell Neurosci. 2013;7(November):220.PubMedPubMedCentral

20.

Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kälin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock D, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci. 2012;15:827–35.

21.

Alexandrov PN, Dua P, Hill JM, Bhattacharjee S, Zhao Y, Walter J. microRNA (miRNA) speciation in Alzheimer’ s disease (AD) cerebrospinal fluid (CSF) and extracellular fluid (ECF). Int J Biochem Mol Biol. 2012;3:365–73.PubMedPubMedCentral

22.

Müller M, Kuiperij HB, Claassen JA, Küsters B, Verbeek MM. MicroRNAs in Alzheimer’s disease: differential expression in hippocampus and cell-free cerebrospinal fluid. Neurobiol Aging. 2014;35:152–8.CrossRefPubMed

23.

Sala Frigerio C, Lau P, Salta E, Tournoy J, Bossers K, Vandenberghe R, Wallin A, Bjerke M, Zetterberg H, Blennow K, De Strooper B. Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease. Neurology. 2013;81:2103–6.

24.

Liu C-G, Wang J-L, Li L, Xue L-X, Zhang Y-Q, Wang P-C. MicroRNA-135a and -200b, potential Biomarkers for Alzheimer׳s disease, regulate β secretase and amyloid precursor protein. Brain Res. 2014;1583:55–64.CrossRefPubMed

25.

Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T. MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer’s disease. J Alzheimer’s Dis. 2014;39:253–9.

26.

Burgos K, Malenica I, Metpally R, Courtright A, Rakela B, Beach T, Shill H, Adler C, Sabbagh M, Villa S, Tembe W, Craig D, Van Keuren-Jensen K. Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer’s and Parkinson's diseases correlate with disease status and features of pathology. PLoS One. 2014;9:e94839.

27.

Galimberti D, Villa C, Fenoglio C, Serpente M, Ghezzi L, Cioffi SMG, Arighi A, Fumagalli G, Scarpini E. Circulating miRNAs as Potential Biomarkers in Alzheimer’s Disease. J Alzheimers Dis. 2014;42:1261–7.

28.

McKhann G, Knopman DS, Chertkow H, Hymann B, Jack CR, Kawas C, Klunk W, Koroshetz W, Manly J, Mayeux R, Mohs R, Morris J, Rossor M, Scheltens P, Carrillo M, Weintrub S, Phelphs C. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.

29.

Roman G. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1994;43:250–60.CrossRef

30.

McKhann GM. Clinical and Pathological Diagnosis of Frontotemporal Dementia. Arch Neurol. 2001;58:1803.CrossRefPubMed

31.

McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson J a, Ince PG, Bergeron C, Burns a, Miller BL,Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos R a, Wilcock GK, Jellinger K a, Perry RH. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47:1113–24.

32.

Andersen CL, Jensen JL, Ørntoft TF. Normalization of Real-Time Quantitative Reverse Transcription-PCR Data : A Model-Based Variance Estimation Approach to Identify Genes Suited for Normalization, Applied to Bladder and Colon Cancer Data Sets Normalization of Real-Time Quantitative Reverse. Cancer Res. 2004;64:5245–50.CrossRefPubMed

33.

Jolla L. Quantification strategies in real-time PCR Michael W.Pfaffl. 2004. p. 87–112.

34.

Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001;184:101–22.CrossRefPubMed

35.

Sørensen SS, Nygaard A-B, Nielsen M-Y, Jensen K, Christensen T. miRNA Expression Profiles in Cerebrospinal Fluid and Blood of Patients with Acute Ischemic Stroke. Transl Stroke Res. 2014;5:711–8.CrossRefPubMed

36.

Hébert SS, Horré K, Nicolaï L, Bergmans B, Papadopoulou AS, Delacourte A, De Strooper B. MicroRNA regulation of Alzheimer’s Amyloid precursor protein expression. Neurobiol Dis. 2009;33:422–8.

37.

Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330(6012):1774.

38.

Dweep H, Gretz N. miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat Methods. 2015;12:697.CrossRefPubMed

39.

Calero M, Gomez-Ramos A, Calero O, Soriano E, Avila J, Medina M. Additional mechanisms conferring genetic susceptibility to Alzheimer’s disease. Front Cell Neurosci. 2015;9:1–9.CrossRef

40.

Cochran JN, Rush T, Buckingham SC, Roberson ED. The Alzheimer’s disease risk factor CD2AP maintains blood–brain barrier integrity. Hum Mol Genet. 2015;24:6667–74.CrossRefPubMed

41.

Chen XM, Splinter PL, O’Hara SP, LaRusso NF. A cellular micro-RNA, let-7i, regulates toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J Biol Chem. 2007;282:28929–38.CrossRefPubMedPubMedCentral

42.

Zong Y, Wang H, Dong W, Quan X, Zhu H, Xu Y, Huang L, Ma C, Qin C. miR-29c regulates BACE1 protein expression. Brain Res. 2011;1395:108–15.

43.

Lee S-T, Chu K, Jung K-H, Kim JH, Huh J-Y, Yoon H, Park D-K, Lim J-Y, Kim J-M, Jeon D, Ryu H, Lee SK, Kim M, Roh J-K. miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Ann Neurol. 2012;72:269–77.

44.

Tian N, Cao Z, Zhang Y. MiR-206 decreases brain-derived neurotrophic factor levels in a transgenic mouse model of Alzheimer’s disease. Neurosci Bull. 2014;30:191–7.CrossRefPubMed

45.

Ren J, Zhang J, Xu N, Han G, Geng Q, Song J, Li S, Zhao J, Chen H. Signature of circulating MicroRNAs As potential biomarkers in vulnerable coronary artery disease. PLoS One. 2013;8(12):e80738.

46.

Villa C, Fenoglio C, De Riz M, Clerici F, Marcone A, Benussi L, Ghidoni R, Gallone S, Cortini F, Serpente M, Cantoni C, Fumagalli G, Boneschi FM, Cappa S, Binetti G, Franceschi M, Rainero I, Giordana MT, Mariani C, Bresolin N, Scarpini E, Galimberti D. Role of hnRNP-A1 and miR-590-3p in neuronal death: genetics and expression analysis in patients with Alzheimer disease and frontotemporal lobar degeneration. Rejuvenation Res. 2011;14:275–81.

47.

Narasimhan M, Patel D, Vedpathak D, Rathinam M, Henderson G, Mahimainathan L. Identification of Novel microRNAs in Post-Transcriptional Control of Nrf2 Expression and Redox Homeostasis in Neuronal, SH-SY5Y Cells. PLoS One. 2012;7(12):e51111.CrossRefPubMedPubMedCentral

48.

Kumar P, Dezso Z, MacKenzie C, Oestreicher J, Agoulnik S, Byrne M, Bernier F, Yanagimachi M, Aoshima K, Oda Y. Circulating miRNA biomarkers for Alzheimer’s disease. PLoS One. 2013;8:e69807.

49.

Wang T, Chen K, Li H, Dong S, Su N, Liu Y, Cheng Y, Dai J, Yang C, Xiao S. The Feasibility of Utilizing Plasma MiRNA107 and BACE1 Messenger RNA Gene Expression for Clinical Diagnosis of Amnestic Mild Cognitive Impairment. J Clin Psychiatry. 2015;76(2):135–41.

50.

Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, Haas J, Ruprecht K, Paul F, Stähler C, Lang CJ, Meder B, Bartfai T, Meese E, Keller A. A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol. 2013;14:R78.

Title: miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer’s disease and other types of dementia – an exploratory study
Authors: Sofie Sølvsten Sørensen
Ann-Britt Nygaard
Thomas Christensen
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Translational Neurodegeneration / Issue 1/2016
Electronic ISSN: 2047-9158
DOI: https://doi.org/10.1186/s40035-016-0053-5

At a glance: The STEP trials

Springer Medicine

miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer’s disease and other types of dementia – an exploratory study

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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