Abstract
There is no consensus for a blood-based test for the early diagnosis of Alzheimer’s disease (AD). Expression profiling of small non-coding RNA’s, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N=49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N=60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein ɛ4 (APOE ɛ4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cole SL, Vassar R . The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology. J Biol Chem 2008; 283: 29621–29625.
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O et al. Amyloid deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013; 12: 357–367.
Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L . Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5: 228–234.
Krol J, Loedige I, Filipowicz W . The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11: 597–610.
He L, Hannon GJ . MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522–531.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO . Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654–659.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008; 105: 10513–10518.
Bellingham SA, Guo BB, Coleman BM, Hill AF . Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol 2012; 3: 124.
Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10: 1470–1476.
Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 2008; 3: e3694.
Cheng L, Sharples RA, Scicluna BJ, Hill AF . Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 2014; 3. doi:10.3402/jev.v3.23743 (e-pub ahead of print)
Cheng L, Quek CY, Sun X, Bellingham SA, Hill AF . The detection of microRNA associated with Alzheimer's disease in biological fluids using next-generation sequencing technologies. Front Genet 2013; 4: 150.
Coleman BM, Hanssen E, Lawson VA, Hill AF . Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J 2012; 26: 4160–4173.
Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010; 31: 1275–1283.
Ellis KA, Rowe CC, Villemagne VL, Martins RN, Masters CL, Salvado O et al. Addressing population aging and Alzheimer's disease through the Australian imaging biomarkers and lifestyle study: collaboration with the Alzheimer's Disease Neuroimaging Initiative. Alzheimers Dement 2010; 6: 291–296.
Ellis KA, Bush AI, Darby D, De Fazio D, Foster J, Hudson P et al. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int Psychogeriatr 2009; 21: 672–687.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.
Cheng L, Sun X, Scicluna BJ, Coleman BM, Hill AF . Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int 2013; 86: 433–444.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3: 34.
Kirschner MB, Edelman JJ, Kao SC, Vallely MP, van Zandwijk N, Reid G . The impact of hemolysis on cell-free microRNA biomarkers. Front Genet 2013; 4: 94.
Haqqani AS, Delaney CE, Tremblay TL, Sodja C, Sandhu JK, Stanimirovic DB . Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS 2013; 10: 4.
Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 2013; 14: 319.
Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O . Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 2009; 11: 1143–1149.
Mitchell JP, Court J, Mason MD, Tabi Z, Clayton A . Increased exosome production from tumour cell cultures using the Integra CELLine Culture System. J Immunol Methods 2008; 335: 98–105.
Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K et al. A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 2013; 14: R78.
Kumar P, Dezso Z, MacKenzie C, Oestreicher J, Agoulnik S, Byrne M et al. Circulating miRNA biomarkers for Alzheimer's disease. PLoS ONE 2013; 8: e69807.
Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 2013; 4: 2980.
Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R, Hill AF . Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol 2007; 211: 582–590.
Sharples RA, Vella LJ, Nisbet RM, Naylor R, Perez K, Barnham KJ et al. Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J 2008; 22: 1469–1478.
Bellingham SA, Coleman BM, Hill AF . Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res 2012; 40: 10937–10949.
Long JM, Lahiri DK . MicroRNA-101 downregulates Alzheimer's amyloid-beta precursor protein levels in human cell cultures and is differentially expressed. Biochem Biophys Res Commun 2011; 404: 889–895.
Vilardo E, Barbato C, Ciotti M, Cogoni C, Ruberti F . MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem 2010; 285: 18344–18351.
Hebert SS, Papadopoulou AS, Smith P, Galas MC, Planel E, Silahtaroglu AN et al. Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet 2010; 19: 3959–3969.
Finnerty JR, Wang WX, Hebert SS, Wilfred BR, Mao G, Nelson PT . The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol 2010; 402: 491–509.
Augustin R, Endres K, Reinhardt S, Kuhn PH, Lichtenthaler SF, Hansen J et al. Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med Genet 2012; 13: 35.
Kim J, Yoon H, Ramirez CM, Lee SM, Hoe HS, Fernandez-Hernando C . MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression. Exp Neurol 2012; 235: 476–483.
Wang H, Liu J, Zong Y, Xu Y, Deng W, Zhu H et al. miR-106b aberrantly expressed in a double transgenic mouse model for Alzheimer's disease targets TGF-beta type II receptor. Brain Res 2010; 1357: 166–174.
Wang WX, 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.
Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B et al. 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.
Rowe CC, Bourgeat P, Ellis KA, Brown B, Lim YY, Mulligan R et al. Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol 2013; 74: 905–913.
Blennow K, Hampel H, Weiner M, Zetterberg H . Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 2010; 6: 131–144.
Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B et al. Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58: 373–379.
Sala Frigerio C, Lau P, Salta E, Tournoy J, Bossers K, Vandenberghe R et al. Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease. Neurol 2013; 81: 2103–2106.
Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimer's Dement 2011; 7: 386–395 e386.
Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014; 20: 415–418.
Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 2007; 13: 1359–1362.
Rembach A, Watt AD, Wilson WJ, Villemagne VL, Burnham SC, Ellis KA et al. Plasma amyloid-beta levels are significantly associated with a transition toward Alzheimer's disease as measured by cognitive decline and change in neocortical amyloid burden. J Alzheimer's Dis 2014; 40: 95–104.
Acknowledgements
This work was supported by the National Health and Medical Research Council (628946 to AFH and CLM) and project grants from The Judith Jane Mason and Harold Stannett Williams Memorial Foundation and Alzheimer’s Australia (to LC and AFH). LC was supported by a University of Melbourne Early Career Researcher Project Grant for the work and AFH is an Australian Research Council Future Fellow (FT100100560 to AFH). This work was also supported in part by the NHMRC project grant 1071430 to VLV and VLV is supported by an NHMRC Senior Research Fellowship. AIBL was supported by the Science Industry and Endowment Fund (sief.org.au), the McCusker Alzheimer's Research Foundation and the National Health and Medical Research Council via the Dementia Collaborative Research Centres program (DCRC2).
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Rights and permissions
About this article
Cite this article
Cheng, L., Doecke, J., Sharples, R. et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 20, 1188–1196 (2015). https://doi.org/10.1038/mp.2014.127
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2014.127
This article is cited by
-
Systematic review: fluid biomarkers and machine learning methods to improve the diagnosis from mild cognitive impairment to Alzheimer’s disease
Alzheimer's Research & Therapy (2023)
-
Traumatic MicroRNAs: Deconvolving the Signal After Severe Traumatic Brain Injury
Cellular and Molecular Neurobiology (2023)
-
Comprehensive circulating microRNA profile as a supersensitive biomarker for early-stage lung cancer screening
Journal of Cancer Research and Clinical Oncology (2023)
-
Advanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer’s Disease
Cellular and Molecular Neurobiology (2023)
-
The role of microRNAs in neurodegenerative diseases: a review
Cell Biology and Toxicology (2023)