Cited by 209Alzheimer's disease research and treatmentsExtracellular vesicles in diseaseDementia and Cognitive Impairment Research

Subtyping of circulating exosome-bound amyloid β reflects brain plaque deposition

Open access
Lim, Carine Z. J., Zhang, Yan, Chen, Yu, Zhao, Haitao, Stephenson, Mary C., Ho, Nicholas R. Y., Chen, Yuan, Chung, Jaehoon +4 more·2019·Nature Communications

Abstract

Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.

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/s41467-019-09030-2

Cites

10 of 10 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?

  • Lim et al. developed the Amplified Plasmonic Exosome (APEX) platform for multiplexed analysis of exosome populations directly from blood samples of patients with Alzheimer's disease.

    “Lim et al. have developed a highly sensitive analytical platform, termed Amplified Plasmonic Exosome (APEX), designed for multiplexed analysis of exosome populations directly from the blood samples of patients with AD [232].”

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: 40

  1. [1]Masters CL Alzheimer’s disease Nat. Rev. Dis. Prim. 2015 1 15056 10.1038/nrdp.2015.56 27188934 · DOI · Paper page
  2. [2]Ittner LM Götz J Amyloid-β and tau—a toxic pas de deux in Alzheimer’s disease Nat. Rev. Neurosci. 2011 12 65 72 10.1038/nrn2967 21193853 · DOI
  3. [3]Nestor PJ Scheltens P Hodges JR Advances in the early detection of Alzheimer’s disease Nat. Med 2004 10 Suppl S34 S41 10.1038/nrn1433 15298007 · DOI
  4. [4]Winblad B Defeating Alzheimer’s disease and other dementias: a priority for European science and society Lancet Neurol. 2016 15 455 532 10.1016/S1474-4422(16)00062-4 26987701 · DOI · Paper page
  5. [5]Lleó A Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases Nat. Rev. Neurol. 2015 11 41 55 10.1038/nrneurol.2014.232 25511894 · DOI
  6. [6]Villemagne VL Doré V Burnham SC Masters CL Rowe CC Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions Nat. Rev. Neurol. 2018 14 225 236 10.1038/nrneurol.2018.9 29449700 · DOI
  7. [7]Hampel H Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives Nat. Rev. Drug Discov. 2010 9 560 574 10.1038/nrd3115 20592748 · DOI
  8. [9]Lue LF Guerra A Walker DG Amyloid Beta and Tau as Alzheimer’s disease blood biomarkers: promise from new technologies Neurol. Ther. 2017 6 25 36 10.1007/s40120-017-0074-8 PMC5520820 28733956 · DOI
  9. [10]Olsson B CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis Lancet Neurol. 2016 15 673 684 10.1016/S1474-4422(16)00070-3 27068280 · DOI · Paper page
  10. [13]Wang J Gu BJ Masters CL Wang YJ A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain Nat. Rev. Neurol. 2017 13 703 10.1038/nrneurol.2017.147 29027541 · DOI
  11. [14]Colombo M Raposo G Théry C Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles Annu Rev. Cell Dev. Biol. 2014 30 255 289 10.1146/annurev-cellbio-101512-122326 25288114 · DOI · Paper page
  12. [15]Simpson RJ Lim JW Moritz RL Mathivanan S Exosomes: proteomic insights and diagnostic potential Expert Rev. Proteom. 2009 6 267 283 10.1586/epr.09.17 19489699 · DOI
  13. [16]E. L. Andaloussi S Mäger I Breakefield XO Wood MJ Extracellular vesicles: biology and emerging therapeutic opportunities Nat. Rev. Drug Discov. 2013 12 347 357 10.1038/nrd3978 23584393 · DOI · Paper page
  14. [17]Shao H New technologies for analysis of extracellular vesicles Chem. Rev. 2018 118 1917 1950 10.1021/acs.chemrev.7b00534 29384376 PMC6029891 · DOI
  15. [18]Tkach, M., Kowal, J. & Théry, C. Why the need and how to approach the functional diversity of extracellular vesicles. Philos Trans R Soc Lond B Biol Sci. 373, 20160479 (2018). PMC5717434 29158309
  16. [19]Valadi H Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells Nat. Cell Biol. 2007 9 654 659 10.1038/ncb1596 17486113 · DOI · Paper page
  17. [20]Skog J Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers Nat. Cell Biol. 2008 10 1470 1476 10.1038/ncb1800 19011622 PMC3423894 · DOI · Paper page
  18. [21]Shao H Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy Nat. Med 2012 18 1835 1840 10.1038/nm.2994 23142818 PMC3518564 · DOI
  19. [22]Shao H Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma Nat. Commun. 2015 6 6999 10.1038/ncomms7999 25959588 PMC4430127 · DOI
  20. [23]Peinado H Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET Nat. Med 2012 18 883 891 10.1038/nm.2753 22635005 PMC3645291 · DOI · Paper page
  21. [24]Pucci F SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions Science 2016 352 242 246 10.1126/science.aaf1328 26989197 PMC4960636 · DOI
  22. [25]An K Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo Mol. Brain 2013 6 47 10.1186/1756-6606-6-47 24284042 PMC4222117 · DOI
  23. [26]Yuyama K A potential function for neuronal exosomes: sequestering intracerebral amyloid-β peptide FEBS Lett. 2015 589 84 88 10.1016/j.febslet.2014.11.027 25436414 · DOI
  24. [27]Rajendran L Alzheimer’s disease beta-amyloid peptides are released in association with exosomes Proc. Natl Acad. Sci. USA 2006 103 11172 11177 10.1073/pnas.0603838103 16837572 PMC1544060 · DOI · Paper page
  25. [28]Jain PK El-Sayed MA Plasmonic coupling in noble metal nanostructures Chem. Phys. Lett. 2010 487 153 164 10.1016/j.cplett.2010.01.062 · DOI
  26. [29]Brolo A Plasmonics for future biosensors Nat. Photonics 2012 6 709 713 10.1038/nphoton.2012.266 · DOI
  27. [30]Xin H Namgung B Lee LP Nanoplasmonic optical antennas for life sciences and medicine Nat. Rev. Mater. 2018 3 228 243 10.1038/s41578-018-0033-8 · DOI
  28. [31]Im H Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor Nat. Biotechnol. 2014 32 490 495 10.1038/nbt.2886 24752081 PMC4356947 · DOI
  29. [32]Lötvall J Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles J. Extracell. Vesicles 2014 3 26913 10.3402/jev.v3.26913 25536934 PMC4275645 · DOI
  30. [33]Chattopadhyay K Mazumdar S Structural and conformational stability of horseradish peroxidase: effect of temperature and pH Biochemistry 2000 39 263 270 10.1021/bi990729o 10625502 · DOI
  31. [35]Arnold SE Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums Nat. Rev. Neurol. 2018 14 168 181 10.1038/nrneurol.2017.185 29377010 PMC6098968 · DOI · Paper page
  32. [36]Jan A Hartley DM Lashuel HA Preparation and characterization of toxic Abeta aggregates for structural and functional studies in Alzheimer’s disease research Nat. Protoc. 2010 5 1186 1209 10.1038/nprot.2010.72 20539293 · DOI
  33. [38]Benilova I Karran E De Strooper B The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes Nat. Neurosci. 2012 15 349 357 10.1038/nn.3028 22286176 · DOI · Paper page
  34. [39]Ryan TM Ammonium hydroxide treatment of Aβ produces an aggregate free solution suitable for biophysical and cell culture characterization PeerJ 2013 1 e73 10.7717/peerj.73 23678397 PMC3646356 · DOI
  35. [40]Knowles TP Buehler MJ Nanomechanics of functional and pathological amyloid materials Nat. Nanotechnol. 2011 6 469 479 10.1038/nnano.2011.102 21804553 · DOI
  36. [41]Hartl FU Hayer-Hartl M Converging concepts of protein folding in vitro and in vivo Nat. Struct. Mol. Biol. 2009 16 574 581 10.1038/nsmb.1591 19491934 · DOI
  37. [43]Yamin G Teplow DB Pittsburgh Compound-B (PiB) binds amyloid β-protein protofibrils J. Neurochem 2017 140 210 215 10.1111/jnc.13887 27943341 PMC5225051 · DOI
  38. [45]Femminella GD Ferrara N Rengo G The emerging role of microRNAs in Alzheimer’s disease Front Physiol. 2015 6 40 10.3389/fphys.2015.00040 25729367 PMC4325581 · DOI
  39. [46]Heneka MT Golenbock DT Latz E Innate immunity in Alzheimer’s disease Nat. Immunol. 2015 16 229 236 10.1038/ni.3102 25689443 · DOI · Paper page
  40. [48]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

Cited by

Sorted by citations

Authors
Lim, C. Z. J., Zhang, Y., Chen, Y., Zhao, H., Stephenson, M. C., Ho, N. R. Y., Chen, Y., Chung, J., Reilhac, A., Loh, T. P., Chen, C. L. H., & Shao, H.
Affiliations
  • National University of Singapore (SG)
  • Agency for Science, Technology and Research (SG)
Corresponding author
Shao, Huilin
Venue
Nature Communications
Published
2019-03-08
Volume
10
Issue
1
Pages
1144-1144
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2922092934
Cited by
209
References
10
Citations by year
2026: 19 · 2025: 31 · 2024: 34 · 2023: 24 · 2022: 28 · 2021: 37 · 2020: 24 · 2019: 12
FWCI
17.32
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Education, India
  • National Medical Research Council
  • Institute of Molecular and Cell Biology
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • 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
Keywords
Alzheimer's disease, amyloid-beta, exosomes, blood biomarkers, plasmonic nanostructures, amyloid plaques, CD63, positron emission tomography, liquid biopsy
MeSH terms
THP-1 Cells, Alzheimer Disease, Brain, Humans, Neurons, Peptide Fragments, Serum Albumin, Bovine, Biosensing Techniques, Case-Control Studies, Amyloid beta-Peptides, Surface Plasmon Resonance, Cell Line, Tumor, Microfluidic Analytical Techniques, Positron-Emission Tomography, Exosomes, Plaque, Amyloid, Tetraspanin 30, Human Umbilical Vein Endothelial Cells, Protein Aggregates

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