CoChat
Sign Up
Cited by 193Extracellular vesicles in diseaseNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease

Open access
Delpech, Jean-Christophe, Herron, Shawn, Botros, Mina B., Ikezu, Tsuneya·2019·Trends in Neurosciences
DOI 10.1016/j.tins.2019.02.007PMC PMC6486849
Open this paper in CoChat — free account

Abstract

The dynamics of CNS function rely upon omnidirectional communication among CNS cell types. Extracellular vesicles (EVs) have emerged as key mediators of this communication and are actively involved in response to CNS injury, mediating inflammatory response and inflammation-related neuroprotection as they display dual beneficial and detrimental roles. Neuroimmune interactions include communication between neurons and microglia, the resident macrophages within the CNS, and these interactions are a critical mediator of healthy brain functions, mounting an inflammatory response, and disease pathogenesis. This review aims to organize recent research highlighting the role of EVs in health and neurodegenerative disorders, with a specific focus on neuroimmune interactions between neurons and glia in Alzheimer's disease.

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 · 10.1016/j.tins.2019.02.007

Cites

11 of 11 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?

  • In AD, EVs contribute to tau propagation, neuroinflammatory signaling, astrocyte activation, and vascular dysfunction.

    “In AD, EVs contribute to tau propagation, neuroinflammatory signaling, astrocyte activation, and vascular dysfunction. 21 , 22 , 23 , 24 , 25”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [23]

    The EV Crosstalk in CNS Disease section links EVs in AD to tau propagation and neuroinflammation. Neuroimmune Communication with EVs reports astrocyte activation by microglial EVs in rodent experiments, but does not establish that effect specifically in AD. The passages found do not link EVs to vascular dysfunction in AD; the indexed copy provides no page numbers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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: 78

  1. [1]Graner MW (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23 (5), 1541– 57. 19109410 PMC2669426
  2. [3]Mustapic M (2017) Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. Front Neurosci 11, 278. 28588440 PMC5439289
  3. [5]Joshi P (2014) Microglia convert aggregated amyloid-beta into neurotoxic forms through the shedding of microvesicles. Cell Death Differ 21 (4), 582– 93. 24336048 PMC3950321
  4. [7]Colombo M (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30, 255– 89. 25288114
  5. [8]Thery C (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2 (8), 569– 79. 12154376
  6. [9]Zhang J (2015) Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics 13 (1), 17– 24. 25724326 PMC4411500
  7. [10]Nazarenko I (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70 (4), 1668– 78. 20124479
  8. [11]Eldh M (2010) Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One 5 (12), e15353. 21179422 PMC3003701
  9. [12]Carayon K (2011) Proteolipidic composition of exosomes changes during reticulocyte maturation. J Biol Chem 286 (39), 34426– 39. 21828046 PMC3190795
  10. [13]de Jong OG (2012) Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles 1. PMC3760650 24009886
  11. [14]Pusic AD and Kraig RP (2014) Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 62 (2), 284– 99. 24339157 PMC4096126
  12. [15]Fitzner D (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124 (Pt 3), 447– 58. 21242314
  13. [16]Kramer-Albers EM (2007) Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin Appl 1 (11), 1446– 61. 21136642
  14. [17]Antonucci F (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31 (5), 1231– 40. 22246184 PMC3297996
  15. [18]Ciregia F (2017) Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases. Front Mol Neurosci 10, 276. 28912682 PMC5583211
  16. [19]Robbins PD (2017) Extracellular vesicles and aging. Stem Cell Investig 4, 98. PMC5762993 29359137
  17. [20]Szepesi Z (2018) Bidirectional Microglia-Neuron Communication in Health and Disease. Front Cell Neurosci 12, 323. 30319362 PMC6170615
  18. [21]Eyo UB and Wu LJ (2013) Bidirectional microglia-neuron communication in the healthy brain. Neural Plast 2013, 456857. 24078884 PMC3775394
  19. [22]Biber K (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30 (11), 596– 602. 17950926
  20. [23]Caruso S and Poon IKH (2018) Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris. Front Immunol 9, 1486. 30002658 PMC6031707
  21. [25]Weber CE (2015) Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene 34 (37), 4821– 33. 25531323 PMC4476970
  22. [26]Matias D (2018) Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors. Front Cell Neurosci 12, 235. 30123112 PMC6086063
  23. [27]Fitzgerald W (2018) A System of Cytokines Encapsulated in ExtraCellular Vesicles. Sci Rep 8 (1), 8973. 29895824 PMC5997670
  24. [28]Bianco F (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174 (11), 7268– 77. 15905573
  25. [29]Drago F (2017) ATP Modifies the Proteome of Extracellular Vesicles Released by Microglia and Influences Their Action on Astrocytes. Front Pharmacol 8, 910. 29321741 PMC5733563
  26. [30]Kumar A (2017) Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury. J Neuroinflammation 14 (1), 47. 28292310 PMC5351060
  27. [31]Yang Y (2018) Inflammation leads to distinct populations of extracellular vesicles from microglia. J Neuroinflammation 15 (1), 168. 29807527 PMC5972400
  28. [32]Verderio C (2012) Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol 72 (4), 610– 24. 23109155
  29. [33]Takenouchi T (2015) Extracellular ATP induces unconventional release of glyceraldehyde-3-phosphate dehydrogenase from microglial cells. Immunol Lett 167 (2), 116– 24. 26277554
  30. [34]Li JJ (2018) In vivo evidence for the contribution of peripheral circulating inflammatory exosomes to neuroinflammation. J Neuroinflammation 15 (1), 8. 29310666 PMC5759808
  31. [36]Kanninen KM (2016) Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta 1862 (3), 403– 10. 26432482
  32. [38]Lachenal G (2011) Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci 46 (2), 409– 18. 21111824
  33. [39]Budnik V (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17 (3), 160– 72. 26891626 PMC4989863
  34. [40]Fruhbeis C (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11 (7), e1001604. 23874151 PMC3706306
  35. [41]Goldie BJ (2014) Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 42 (14), 9195– 208. 25053844 PMC4132720
  36. [42]Morel L (2013) Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 288 (10), 7105– 16. 23364798 PMC3591620
  37. [43]Bahrini I (2015) Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia. Sci Rep 5, 7989. 25612542 PMC4303875
  38. [45]Frohlich D (2014) Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond B Biol Sci 369 (1652). PMC4142031 25135971
  39. [46]Kocur M (2015) IFNbeta secreted by microglia mediates clearance of myelin debris in CNS autoimmunity. Acta Neuropathol Commun 3, 20. 25853624 PMC4383054
  40. [48]Paolicelli RC (2018) Cell-to-cell Communication by Extracellular Vesicles: Focus on Microglia. Neuroscience. 29660443
  41. [50]Prada I (2018) Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations. Acta Neuropathol 135 (4), 529– 550. 29302779 PMC5978931
  42. [51]Taylor AR (2007) Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev Neurobiol 67 (13), 1815– 29. 17701989
  43. [52]Proia P (2008) Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor. Int J Mol Med 21 (1), 63– 7. 18097617
  44. [53]Wang S (2011) Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci 31 (20), 7275– 90. 21593312 PMC6622588
  45. [54]DeLeo AM and Ikezu T (2018) Extracellular Vesicle Biology in Alzheimer’s Disease and Related Tauopathy. J Neuroimmune Pharmacol 13 (3), 292– 308. 29185187 PMC5972041
  46. [55]Yuyama K (2015) A potential function for neuronal exosomes: sequestering intracerebral amyloid-beta peptide. FEBS Lett 589 (1), 84– 8. 25436414
  47. [56]Yuyama K and Igarashi Y (2016) Physiological and pathological roles of exosomes in the nervous system. Biomol Concepts 7 (1), 53– 68. 26812803
  48. [57]Yuyama K and Igarashi Y (2017) Exosomes as Carriers of Alzheimer’s Amyloid-ss. Front Neurosci 11, 229. 28487629 PMC5403946
  49. [58]Rajendran L (2006) Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A 103 (30), 11172– 7. 16837572 PMC1544060
  50. [60]Dinkins MB (2014) Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 35 (8), 1792– 800. 24650793 PMC4035236
  51. [61]Asai H (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18 (11), 1584– 93. 26436904 PMC4694577
  52. [62]Yuyama K (2012) Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J Biol Chem 287 (14), 10977– 89. 22303002 PMC3322859
  53. [63]Gouwens LK (2018) Abeta42 Protofibrils Interact with and Are Trafficked through Microglial-Derived Microvesicles. ACS Chem Neurosci 9 (6), 1416– 1425. 29543435
  54. [64]Eitan E (2016) Extracellular Vesicle-Associated Abeta Mediates Trans-Neuronal Bioenergetic and Ca(2+)-Handling Deficits in Alzheimer’s Disease Models. NPJ Aging Mech Dis 2. PMC5137253 27928512
  55. [65]Goetzl EJ (2016) Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer’s disease. FASEB J 30 (11), 3853– 3859. 27511944 PMC5067254
  56. [66]Polanco JC (2016) Extracellular Vesicles Isolated from the Brains of rTg4510 Mice Seed Tau Protein Aggregation in a Threshold-dependent Manner. J Biol Chem 291 (24), 12445– 66. 27030011 PMC4933440
  57. [68]Medina M and Avila J (2014) The role of extracellular Tau in the spreading of neurofibrillary pathology. Front Cell Neurosci 8, 113. 24795568 PMC4005959
  58. [69]Agosta F (2014) Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease. Ann Neurol 76 (6), 813– 25. 25087695
  59. [70]Clayton KA (2017) Alzheimer’s Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Front Neurosci 11, 680. 29311768 PMC5733046
  60. [71]S ELA (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12 (5), 347– 57. 23584393
  61. [72]Raposo G and Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200 (4), 373– 83. 23420871 PMC3575529
  62. [73]Gyorgy B (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68 (16), 2667– 88. 21560073 PMC3142546
  63. [74]Andreu Z and Yanez-Mo M (2014) Tetraspanins in extracellular vesicle formation and function. Front Immunol 5, 442. 25278937 PMC4165315
  64. [75]Abels ER and Breakefield XO (2016) Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol Neurobiol 36 (3), 301– 12. 27053351 PMC5546313
  65. [76]Mulcahy LA (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3. PMC4122821 25143819
  66. [77]Grad LI (2015) From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis. Neurobiol Dis 77, 257– 65. 25701498
  67. [78]Basso M (2013) Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem 288 (22), 15699– 711. 23592792 PMC3668729
  68. [79]Ferrara D (2018) Role of Extracellular Vesicles in Amyotrophic Lateral Sclerosis. Front Neurosci 12, 574. 30174585 PMC6107782
  69. [80]Zhang X (2016) Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington’s Disease: Background and Evaluation in Cell Culture. Cell Mol Neurobiol 36 (3), 459– 70. 26951563 PMC5844350
  70. [81]Saenz-Cuesta M (2014) Extracellular Vesicles in Multiple Sclerosis: What are They Telling Us? Front Cell Neurosci 8, 100. 24734004 PMC3975116
  71. [82]Minagar A and Alexander JS (2003) Blood-brain barrier disruption in multiple sclerosis. Mult Scler 9 (6), 540– 9. 14664465
  72. [83]Prada I (2013) Classical and unconventional pathways of vesicular release in microglia. Glia 61 (7), 1003– 17. 23625857
  73. [84]Shi M (2014) Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 128 (5), 639– 650. 24997849 PMC4201967
  74. [85]Danzer KM (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7, 42. 22920859 PMC3483256
  75. [86]Fevrier B (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101 (26), 9683– 8. 15210972 PMC470735
  76. [87]Bellingham SA (2012) Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res 40 (21), 10937– 49. 22965126 PMC3505968
  77. [88]McKee AC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136 (Pt 1), 43– 64. 23208308 PMC3624697
  78. [89]Stern RA (2016) Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. J Alzheimers Dis 51 (4), 1099– 109. 26890775 PMC4833534

Cited by

Sorted by citations

Authors
Delpech, J.-C., Herron, S., Botros, M. B., & Ikezu, T.
Affiliations
Boston University (US)
Corresponding author
Ikezu, Tsuneya
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2019-05
Volume
42
Issue
5
Pages
361-372
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2019.02.007
PMC
PMC6486849
OpenAlex
W2924831238
Cited by
193
References
11
Citations by year
2026: 25 · 2025: 13 · 2024: 28 · 2023: 32 · 2022: 27 · 2021: 34 · 2020: 24 · 2019: 9
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • Nancy Lurie Marks Family Foundation
  • Robert E. Landreth and Dona Landreth Family Foundation
  • BrightFocus Foundation (A2016551S)
  • Cure Alzheimer’s Fund (NIH R01AG054672, RF1AG054199, R56AG057469, 5T32GM008541)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
extracellular vesicles, neuroimmune interactions, neurons, microglia, glia, neuroinflammation, neuroprotection, central nervous system injury, neurodegenerative diseases, Alzheimer's disease, intercellular communication
MeSH terms
Extracellular Vesicles, Alzheimer Disease, Animals, Brain, Health Status, Humans, Neuroglia, Neurons, Neuroimmunomodulation, Microglia, Neurodegenerative Diseases

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