CoChat
Sign Up
Cited by 121Extracellular vesicles in diseaseDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

A combined miRNA-piRNA signature to detect Alzheimer’s disease

Open access
Jain, Gaurav, Stuendl, Anne, Rao, Pooja, Berulava, Tea, Pena Centeno, Tonatiuh, Kaurani, Lalit, Burkhardt, Susanne, Delalle, Ivana +13 more·2019·Translational Psychiatry
DOI 10.1038/s41398-019-0579-2PMC PMC6779890
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder causing huge emotional and economic burden to our societies. An effective therapy has not been implicated yet, which is in part also due to the fact that pathological changes occur years before clinical symptoms manifest. Thus, there is a great need for the development of a translatable biomarker. Recent evidence highlights microRNAs as candidate biomarkers. In this study, we use next-generation sequencing to study the small noncoding RNAome (sncRNAome) in exosomes derived from human cerebrospinal fluid (CSF). We show that the sncRNAome from CSF-derived exosomes is dominated not only by microRNAs (miRNAs) but also by PIWI-interacting RNAs (piRNAs). We define a combined signature consisting of three miRNAs and three piRNAs that are suitable to detect AD with an AUC of 0.83 in a replication cohort and furthermore predict the conversion of mild–cognitive impaired (MCI) patients to AD dementia with an AUC of 0.86 for the piRNA signature. When combining the smallRNA signature with pTau and Aβ 42/40 ratio the AUC reaches 0.98. Our study reports a novel exosomal small noncoding RNA signature to detect AD pathology and provides the first evidence that in addition to miRNAs, piRNAs should also be considered as a candidate biomarker for AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41398-019-0579-2

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 64

  1. [1]Fischer A Targeting histone-modifications in Alzheimer’s disease. What is the evidence that this is a promising therapeutic avenue? Neuropsychopharmacology 2014 80 95 012 24486385
  2. [4]Shi, Y. & Holtzman, D. M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol.18, 759–772 (2018). PMC6425488 30140051
  3. [5]Bateman RJ Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease N. Engl. J. Med. 2012 367 795 804 10.1056/NEJMoa1202753 22784036 PMC3474597 · DOI · Paper page
  4. [6]Molinuevo JL Current state of Alzheimer’s fluid biomarkers Acta Neuropathol. 2018 136 821 853 10.1007/s00401-018-1932-x 30488277 PMC6280827 · DOI · Paper page
  5. [7]Witwer KW Circulating MicroRNA biomarker studies: pitfalls and potential solutions Clin. Chem. 2015 61 56 63 10.1373/clinchem.2014.221341 25391989 · DOI · Paper page
  6. [8]Salta E De Strooper B Noncoding RNAs in neurodegeneration Nat. Rev. Neurosci. 2017 18 627 640 10.1038/nrn.2017.90 28855739 · DOI · Paper page
  7. [9]Gurtan, A. M. & Sharp, P. A. The role of miRNAs in regulating gene expression networks. J. Mol. Biol.425, 3582–3600 (2013). PMC3757117 23500488
  8. [10]Gao J A novel pathway regulates memory and plasticity via SIRT1 and miR-134 Nature 2010 466 1105 1109 10.1038/nature09271 20622856 PMC2928875 · DOI · Paper page
  9. [11]Zovoilis A microRNA-34c is a novel target to treat dementias EMBO J. 2011 30 4299 4308 10.1038/emboj.2011.327 21946562 PMC3199394 · DOI · Paper page
  10. [12]Lin Q The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory Nat. Neurosci. 2011 14 1115 1117 10.1038/nn.2891 21841775 · DOI · Paper page
  11. [13]Griggs EM Young EJ Rumbaugh G Miller CA MicroRNA-182 regulates amygdala-dependent memory formation J. Neurosci. 2013 33 1734 1740 10.1523/JNEUROSCI.2873-12.2013 23345246 PMC3711533 · DOI
  12. [14]Hébert SS Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression Proc. Natl Acad. Sci. USA 2008 205 6415 6420 10.1073/pnas.0710263105 PMC2359789 18434550 · DOI · Paper page
  13. [15]Nelson PT Wang WX MiR-107 is reduced in Alzheimer’s disease brain neocortex: validation study J. Alzheimers Dis. 2010 21 75 79 10.3233/JAD-2010-091603 20413881 PMC2910235 · DOI · Paper page
  14. [16]Schonrock N Neuronal microRNA deregulation in response to Alzheimer’s disease amyloid-beta PLoS ONE 2010 5 e11070 10.1371/journal.pone.0011070 20552018 PMC2884018 · DOI · Paper page
  15. [17]Delay C Mandemakers W Hébert SS MicroRNAs in Alzheimer’s disease Neurobiol. Dis. 2012 46 285 290 10.1016/j.nbd.2012.01.003 22285895 · DOI · Paper page
  16. [18]Sierksma A Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology Mol. Neurodegener. 2018 12 54 10.1186/s13024-018-0285-1 PMC6186090 30314521 · DOI · Paper page
  17. [19]El Fatimy R MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways Acta Neuropathol. 2018 136 537 555 10.1007/s00401-018-1880-5 29982852 PMC6132948 · DOI
  18. [21]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 35 152 158 10.1016/j.neurobiolaging.2013.07.005 23962497 · DOI
  19. [23]Lusardi TA MicroRNAs in human cerebrospinal fluid as biomarkers for Alzheimer’s disease J. Alzheimers Dis. 2017 55 1223 1233 10.3233/JAD-160835 27814298 PMC5587208 · DOI
  20. [24]Riancho J MicroRNA profile in patients with Alzheimer’s disease: analysis of miR-9-5p and miR-598 in raw and exosome enriched cerebrospinal fluid samples J. Alzheimers Dis. 2017 57 483 491 10.3233/JAD-161179 28269782 · DOI · Paper page
  21. [25]Tietje A Maron KN Wei Y Feliciano DM Cerebrospinal fluid extracellular vesicles undergo age dependent declines and contain known and novel non-coding RNAs PLoS ONE 2014 9 e113116 10.1371/journal.pone.0113116 25420022 PMC4242609 · DOI
  22. [26]Akers JC miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients J. Neurooncol. 2015 132 205 216 10.1007/s11060-015-1784-3 PMC4459648 25903655 · DOI
  23. [27]Gui Y Liu H Zhang L Lv W Hu X Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease Oncotarget 2015 6 37043 37053 10.18632/oncotarget.6158 26497684 PMC4741914 · DOI · Paper page
  24. [28]Chaput N Théry C Exosomes: immune properties and potential clinical implementations Semin. Immunopathol. 2011 33 419 440 10.1007/s00281-010-0233-9 21174094 · DOI
  25. [29]Hu, G., Drescher, K. M. & Chen, X. M. Exosomal miRNAs: biological properties and therapeutic potential. Front. Genet. 10.3389/fgene.2012.00056 (2012). PMC3330238 22529849 · DOI
  26. [30]Schneider A Mandelkow E Tau-based treatment strategies in neurodegenerative diseases Neurotherapeutics 2008 5 443 457 10.1016/j.nurt.2008.05.006 18625456 PMC5084246 · DOI
  27. [31]McKhann G 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 10.1212/WNL.34.7.939 6610841 · DOI · Paper page
  28. [33]Petersen RC Mild cognitive impairment: clinical characterization and outcome Arch. Neurol. 1999 56 303 308 10.1001/archneur.56.3.303 10190820 · DOI · Paper page
  29. [34]Winblad B Mild cognitive impairment-beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment J. Intern. Med. 2004 256 240 246 10.1111/j.1365-2796.2004.01380.x 15324367 · DOI · Paper page
  30. [35]Kornhuber J Early and differential diagnosis of dementia and mild cognitive impairment: design and cohort baseline characteristics of the German Dementia Competence Network Dement. Geriatr. Cogn. Disord. 2009 27 404 417 10.1159/000210388 19339779 · DOI
  31. [36]Morris JC The Clinical Dementia Rating (CDR): current version and scoring rules Neurology 1999 43 2412 2414 10.1212/WNL.43.11.2412-a 8232972 · DOI · Paper page
  32. [37]Folstein MF Folstein SE McHugh PR Mini-mental state. A practical method for grading the cognitive state of patients for the clinician J. Psychiatr. Res. 1975 12 189 198 10.1016/0022-3956(75)90026-6 1202204 · DOI · Paper page
  33. [38]Strauss K Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease J. Biol. Chem. 2010 285 26279 26288 10.1074/jbc.M110.134775 20554533 PMC2924046 · DOI
  34. [39]Stuendl A Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies Brain 2016 139 481 494 10.1093/brain/awv346 26647156 PMC4805087 · DOI · Paper page
  35. [40]Kunadt M Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation Acta Neuropathol. 2015 129 695 713 10.1007/s00401-015-1408-1 25778619 PMC4405286 · DOI
  36. [41]Durbin BP Hardin JS Hawkins DM Rocke DM A variance-stabilizing transformation for gene-expression microarray data Bioinformatics 2002 18 S105 S110 10.1093/bioinformatics/18.suppl_1.S105 12169537 · DOI
  37. [42]Huber, W., von Heydebreck, A., Sültmann, H., Poustka, A. & Vingron, M. Parameter estimation for the calibration and variance stabilization of microarray data. Stat. Appl. Genet. Mol. Biol.2, 3 (2003). 16646781
  38. [43]Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, 10.1186/gb-2010-1111-1110-r1106 (2010). PMC3218662 20979621 · DOI
  39. [44]Ripley Brian D The R Project in Statistical Computing MSOR Connections 2001 1 1 23 25 10.11120/msor.2001.01010023 · DOI
  40. [45]Risso D Ngai J Speed TP Dudoit S Normalization of RNA-seq data using factor analysis of control genes or samples Nat. Biotechnol. 2014 32 896 10.1038/nbt.2931 25150836 PMC4404308 · DOI · Paper page
  41. [49]Danka Mohammed Chand Parvez Rhee Hwanseok Phee Bong-Kwan Kim Kunhyung Kim Hee-Jin Lee Hyehyeon Park Jung Hoon Jung Jung Hee Kim Jeong Yeon Kim Hyoung-Chin Park Sang Ki Nam Hong Gil Kim Keetae miR-204 downregulates EphB2 in aging mouse hippocampal neurons Aging Cell 2016 15 2 380 388 10.1111/acel.12444 26799631 PMC4783348 · DOI
  42. [50]Landry CD Kandel ER Rajasethupathy P New mechanisms in memory storage: piRNAs and epigenetics Trends Neurosci. 2013 36 535 542 10.1016/j.tins.2013.05.004 23827695 · DOI
  43. [51]Zhang J Exosome and exosomal microRNA: trafficking, sorting, and function Genomics Proteom. Bioinform. 2015 12 17 24 10.1016/j.gpb.2015.02.001 PMC4411500 25724326 · DOI
  44. [52]Taylor DD Gercel-Taylor C MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer Gynecol. Oncol. 2008 110 13 21 10.1016/j.ygyno.2008.04.033 18589210 · DOI
  45. [53]Rabinowits G Gerçel-Taylor C Day JM Taylor DD Kloecker GH Exosomal microRNA: a diagnostic marker for lung cancer Clin. Lung Cancer 2009 10 42 46 10.3816/CLC.2009.n.006 19289371 · DOI
  46. [54]Wittmann J Jäck HM Serum microRNAs as powerful cancer biomarkers Biochim. Biophys. Acta 2010 1806 200 207 20637263
  47. [55]Yassouridis A Ludwig T Steiger A Leisch F A new way of identifying biomarkers in biomedical basic-research studies PLoS ONE 2012 7 e35741 10.1371/journal.pone.0035741 22606233 PMC3350515 · DOI
  48. [56]Croce N NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection? Mol. Cell. Biochem. 2013 376 189 195 10.1007/s11010-013-1567-0 23358924 · DOI
  49. [58]Lau P Alteration of the microRNA network during the progression of Alzheimer’s disease EMBO Mol. Med. 2013 5 1613 1634 10.1002/emmm.201201974 24014289 PMC3799583 · DOI · Paper page
  50. [59]Oddo S The role of mTOR signaling in Alzheimer disease Front. Biosci. 2012 4 941 10.2741/s310 PMC4111148 22202101 · DOI
  51. [60]Rani V Deshmukh R Jaswal P Kumar P Bariwal J Alzheimer’s disease: is this a brain specific diabetic condition? Physiol. Behav. 2016 1 259 267 10.1016/j.physbeh.2016.05.041 27235734 · DOI
  52. [61]Iyalomhe O The role of hypoxia-inducible factor 1 in mild cognitive impairment Cell Mol. Neurobiol. 2016 2017 6 PMC5435557 27858285
  53. [62]Dansokho C Heneka MT Neuroinflammatory responses in Alzheimer’s disease J. Neural Transm. 2018 125 771 779 10.1007/s00702-017-1831-7 29273951 · DOI
  54. [63]George S Petit GH Gouras GK Brundin P Olsson R Nonsteroidal selective androgen receptor modulators and selective estrogen receptor β agonists moderate cognitive deficits and amyloid-β levels in a mouse model of Alzheimer’s disease ACS Chem. Neurosci. 2013 4 1537 1548 10.1021/cn400133s 24020966 PMC3867967 · DOI
  55. [64]Sanchez-Mejia RO Mucke L Phospholipase A2 and arachidonic acid in Alzheimer’s disease Biochim. Biophys. Acta 2010 1801 784 790 10.1016/j.bbalip.2010.05.013 20553961 PMC3024142 · DOI
  56. [65]Rao, P., Benito, E. & Fischer, A. MicroRNAs as biomarkers for CNS disease. Front. Mol. Neurosci. 6, 39 (2013). PMC3840814 24324397
  57. [66]Zendjabil M Circulating microRNAs as novel biomarkers of Alzheimer’s disease Clin. Chim. Acta 2018 484 99 104 10.1016/j.cca.2018.05.039 29800558 · DOI
  58. [67]Yagi Y Next-generation sequencing-based small RNA profiling of cerebrospinal fluid exosomes Neurosci. Lett. 2017 1 48 57 10.1016/j.neulet.2016.10.042 27780738 · DOI
  59. [68]Zhang Y Hypothalamic stem cells control ageing speed partly through exosomal miRNAs Nature 2017 548 52 57 10.1038/nature23282 28746310 PMC5999038 · DOI · Paper page
  60. [69]Haramati S MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34 J. Neurosci. 2011 31 14191 14203 10.1523/JNEUROSCI.1673-11.2011 21976504 PMC6623664 · DOI · Paper page
  61. [70]Agís-Balboa RC Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia EMBO J. 2017 36 2815 2828 10.15252/embj.201796821 28768717 PMC5623844 · DOI
  62. [71]Müller M MicroRNA-29a is a candidate biomarker for Alzheimer’s disease in cell-free cerebrospinal fluid Mol. Neurobiol. 2016 53 2894 2899 10.1007/s12035-015-9156-8 25895659 PMC4902829 · DOI
  63. [73]Bajic V Spremo-Potparevic B Zivkovic L Isenovic ER Arendt T Cohesion and the aneuploid phenotype in Alzheimer’s disease: a tale of genome instability Neurosci. Biobehav. Rev. 2015 55 365 374 10.1016/j.neubiorev.2015.05.010 26003528 · DOI
  64. [74]Lu J Clark AG Population dynamics of PIWI-interacting RNAs (piRNAs) and their targets in Drosophila Genome Res. 2010 20 212 227 10.1101/gr.095406.109 19948818 PMC2813477 · DOI

Cited by

Sorted by citations

Authors
Jain, G., Stuendl, A., Rao, P., Berulava, T., Pena Centeno, T., Kaurani, L., Burkhardt, S., Delalle, I., Kornhuber, J., Hüll, M., Maier, W., Peters, O., Esselmann, H., Schulte, C., Deuschle, C., Synofzik, M., Wiltfang, J., Mollenhauer, B., Maetzler, W., Schneider, A., & Fischer, A.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Boston University (US)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University Medical Center Freiburg (DE)
  • University of Bonn (DE)
  • Universitätsmedizin Göttingen (DE)
Corresponding author
Schneider, Anja
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-10-07
Volume
9
Issue
1
Pages
250-250
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-019-0579-2
PMC
PMC6779890
OpenAlex
W2977973527
Cited by
121
References
9
Citations by year
2026: 6 · 2025: 19 · 2024: 15 · 2023: 8 · 2022: 25 · 2021: 33 · 2020: 15
FWCI
6.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MACAU: Open Access Repository of Kiel University (University Library Kiel) (publishedVersion, cc-by)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, other-oa)
Funders
  • Michael J. Fox Foundation for Parkinson's Research
  • Universidade de Aveiro (UID/BIM/04501/2013)
  • Universitätsmedizin Göttingen
  • Deutsche Forschungsgemeinschaft (648898, Fi981-4, 179/1‐1/2013, 01GQ1421A, Fi981 11-1, KFO241)
  • Bundesministerium für Bildung und Forschung (01ZX1314D, 01GQ1421A)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Hans und Ilse Breuer-Stiftung
  • Fundação para a Ciência e a Tecnologia (UID/BIM/04501/2013)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, microRNA, piRNA, exosomes, cerebrospinal fluid, small RNA, biomarkers, mild cognitive impairment, tau protein, amyloid-beta 42/40 ratio, diagnostic signature
MeSH terms
Adult, Aged, Alzheimer Disease, Female, Germany, Humans, Male, Middle Aged, Peptide Fragments, Cohort Studies, Biomarkers, Amyloid beta-Peptides, Area Under Curve, RNA, Small Interfering, MicroRNAs, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review