Skip to main content

Advertisement

SpringerLink
Log in

Exosomes in Acquired Neurological Disorders: New Insights into Pathophysiology and Treatment

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Exosomes are endogenous nanovesicles that play critical roles in intercellular signaling by conveying functional genetic information and proteins between cells. Exosomes readily cross the blood-brain barrier and have promise as therapeutic delivery vehicles that have the potential to specifically deliver molecules to the central nervous system (CNS). This unique feature also makes exosomes attractive as biomarkers in diagnostics, prognostics, and therapeutics in the context of multiple significant public health conditions, including acquired neurological disorders. The purpose of this review is to summarize the state of the science surrounding the relevance of extracellular vesicles (EVs), particularly exosomes, to acquire neurological disorders, specifically traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. In total, ten research articles were identified that examined exosomes in the context of TBI, SCI, or stroke; these manuscripts were reviewed and synthesized to further understand the current role of exosomes in the context of acquired neurological disorders. Of the ten published studies, four focused exclusively on TBI, one on both TBI and SCI, and five on ischemic stroke; notably, eight of the ten studies were limited to pre-clinical samples. The present review is the first to discuss the current body of knowledge surrounding the role of exosomes in the pathophysiology, diagnosis, and prognosis, as well as promising therapeutic strategies in TBI, SCI, and stroke research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Akers JC, Gonda D, Kim R, Carter BS, Chen CC (2013) Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neuro-Oncol 113(1):1–11. https://doi.org/10.1007/s11060-013-1084-8

    Article  Google Scholar 

  2. Edgar JR (2016) Q&A: what are exosomes, exactly? BMC Biol 14:46. https://doi.org/10.1186/s12915-016-0268-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Taylor DD, Zacharias W, Gercel-Taylor C (2011) Exosome isolation for proteomic analyses and RNA profiling. Methods Mol Biol 728:235–246. https://doi.org/10.1007/978-1-61779-068-3_15

    Article  CAS  PubMed  Google Scholar 

  4. van Niel G, D’Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19(4):213–228. https://doi.org/10.1038/nrm.2017.125

    Article  CAS  PubMed  Google Scholar 

  5. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17(7):879–887. https://doi.org/10.1093/intimm/dxh267

    Article  CAS  PubMed  Google Scholar 

  6. Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R, Hill AF (2007) Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol 211(5):582–590. https://doi.org/10.1002/path.2145

    Article  CAS  PubMed  Google Scholar 

  7. Ogawa Y, Miura Y, Harazono A, Kanai-Azuma M, Akimoto Y, Kawakami H, Yamaguchi T, Toda T et al (2011) Proteomic analysis of two types of exosomes in human whole saliva. Biol Pharm Bull 34(1):13–23

    Article  CAS  PubMed  Google Scholar 

  8. Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101(36):13368–13373. https://doi.org/10.1073/pnas.0403453101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qin W, Tsukasaki Y, Dasgupta S, Mukhopadhyay N, Ikebe M, Sauter ER (2016) Exosomes in human breast milk promote EMT. Clin Cancer Res 22(17):4517–4524. https://doi.org/10.1158/1078-0432.CCR-16-0135

    Article  CAS  PubMed  Google Scholar 

  10. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–593. https://doi.org/10.1038/nri2567

    Article  CAS  PubMed  Google Scholar 

  11. Hirshman BR, Kras RT, Akers JC, Carter BS, Chen CC (2016) Extracellular vesicles in molecular diagnostics: an overview with a focus on CNS diseases. Adv Clin Chem 76:37–53. https://doi.org/10.1016/bs.acc.2016.05.005

    Article  CAS  PubMed  Google Scholar 

  12. Prada I, Meldolesi J (2016) Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets. Int J Mol Sci 17(8). https://doi.org/10.3390/ijms17081296

    Article  PubMed Central  Google Scholar 

  13. Yoon YJ, Kim OY, Gho YS (2014) Extracellular vesicles as emerging intercellular communicasomes. BMB Rep 47(10):531–539

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y (2015) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 122(4):856–867. https://doi.org/10.3171/2014.11.jns14770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Harrison EB, Hochfelder CG, Lamberty BG, Meays BM, Morsey BM, Kelso ML, Fox HS, Yelamanchili SV (2016) Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation. FEBS Open Bio 6(8):835–846. https://doi.org/10.1002/2211-5463.12092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Rivero Vaccari JP, Brand F 3rd, Adamczak S, Lee SW, Perez-Barcena J, Wang MY, Bullock MR, Dietrich WD et al (2016) Exosome-mediated inflammasome signaling after central nervous system injury. J Neurochem 136(Suppl 1):39–48. https://doi.org/10.1111/jnc.13036

    Article  CAS  PubMed  Google Scholar 

  17. Yang J, Gao F, Zhang Y, Liu Y, Zhang D (2015) Buyang Huanwu Decoction (BYHWD) enhances Angiogenic effect of mesenchymal stem cell by upregulating VEGF expression after focal cerebral ischemia. J Mol Neurosci 56(4):898–906. https://doi.org/10.1007/s12031-015-0539-0

    Article  CAS  PubMed  Google Scholar 

  18. Ji Q, Ji Y, Peng J, Zhou X, Chen X, Zhao H, Xu T, Chen L et al (2016) Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One 11(9):e0163645. https://doi.org/10.1371/journal.pone.0163645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ (2016) Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A 113(1):170–175. https://doi.org/10.1073/pnas.1522297113

    Article  CAS  PubMed  Google Scholar 

  20. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA et al (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 4(10):1131–1143. https://doi.org/10.5966/sctm.2015-0078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ophelders DR, Wolfs TG, Jellema RK, Zwanenburg A, Andriessen P, Delhaas T, Ludwig AK, Radtke S et al (2016) Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med 5(6):754–763. https://doi.org/10.5966/sctm.2015-0197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, Frassetto L, Petersen RC et al (2015) Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J 29(2):589–596. https://doi.org/10.1096/fj.14-262048

    Article  CAS  PubMed  Google Scholar 

  23. Chen F, Du Y, Esposito E, Liu Y, Guo S, Wang X, Lo EH, Xing C et al (2015) Effects of focal cerebral ischemia on exosomal versus serum miR126. Transl Stroke Res 6(6):478–484. https://doi.org/10.1007/s12975-015-0429-3

    Article  CAS  PubMed  Google Scholar 

  24. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C et al (2015) Proteomics. Tissue-based map of the human proteome. Science (New York, NY) 347(6220):1260419. https://doi.org/10.1126/science.1260419

    Article  CAS  Google Scholar 

  25. Ko J, Hemphill MA, Gabrieli D, Wu L, Yelleswarapu V, Lawrence G, Pennycooke W, Singh A et al (2016) Smartphone-enabled optofluidic exosome diagnostic for concussion recovery. Sci Rep 6:31215. https://doi.org/10.1038/srep31215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Momen-Heravi F, Balaj L, Alian S, Mantel PY, Halleck AE, Trachtenberg AJ, Soria CE, Oquin S et al (2013) Current methods for the isolation of extracellular vesicles. Biol Chem 394(10):1253–1262. https://doi.org/10.1515/hsz-2013-0141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Andras IE, Toborek M (2016) Extracellular vesicles of the blood-brain barrier. Tissue Barriers 4(1):e1131804. https://doi.org/10.1080/21688370.2015.1131804

    Article  CAS  PubMed  Google Scholar 

  28. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659. https://doi.org/10.1038/ncb1596

    Article  CAS  PubMed  Google Scholar 

  29. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476. https://doi.org/10.1038/ncb1800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21. https://doi.org/10.1016/j.ygyno.2008.04.033

    Article  CAS  PubMed  Google Scholar 

  31. Kesimer M, Scull M, Brighton B, DeMaria G, Burns K, O'Neal W, Pickles RJ, Sheehan JK (2009) Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J 23(6):1858–1868. https://doi.org/10.1096/fj.08-119131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Verma M, Lam TK, Hebert E, Divi RL (2015) Extracellular vesicles: potential applications in cancer diagnosis, prognosis, and epidemiology. BMC Clin Pathol 15:6. https://doi.org/10.1186/s12907-015-0005-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tatischeff I, Bomsel M, de Paillerets C, Durand H, Geny B, Segretain D, Turpin E, Alfsen A (1998) Dictyostelium discoideum cells shed vesicles with associated DNA and vital stain Hoechst 33342. Cell Mol Life Sci 54(5):476–487. https://doi.org/10.1007/s000180050176

    Article  CAS  PubMed  Google Scholar 

  34. Albuquerque PC, Nakayasu ES, Rodrigues ML, Frases S, Casadevall A, Zancope-Oliveira RM, Almeida IC, Nosanchuk JD (2008) Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes. Cell Microbiol 10(8):1695–1710. https://doi.org/10.1111/j.1462-5822.2008.01160.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Regente M, Corti-Monzon G, Maldonado AM, Pinedo M, Jorrin J, de la Canal L (2009) Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett 583(20):3363–3366. https://doi.org/10.1016/j.febslet.2009.09.041

    Article  CAS  PubMed  Google Scholar 

  36. Dermietzel R, Venjakob K, Brettschneider H (1972) Occurrence of extracellular synaptic vesicles in the autonomic nervous system. Naturwissenschaften 59(3):125–126

    Article  CAS  PubMed  Google Scholar 

  37. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97(2):329–339

    Article  CAS  PubMed  Google Scholar 

  38. Taylor DD, Doellgast GJ (1979) Quantitation of peroxidase-antibody binding to membrane fragments using column chromatography. Anal Biochem 98(1):53–59

    Article  CAS  PubMed  Google Scholar 

  39. Kang CS, Ban M, Choi EJ, Moon HG, Jeon JS, Kim DK, Park SK, Jeon SG et al (2013) Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One 8(10):e76520. https://doi.org/10.1371/journal.pone.0076520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Madison MN, Jones PH, Okeoma CM (2015) Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex. Virology 482:189–201. https://doi.org/10.1016/j.virol.2015.03.040

    Article  CAS  PubMed  Google Scholar 

  41. Carmichael ST (2016) The 3 Rs of stroke biology: radial, relayed, and regenerative. Neurotherapeutics 13(2):348–359. https://doi.org/10.1007/s13311-015-0408-0

    Article  CAS  PubMed  Google Scholar 

  42. Vemuganti R, Hall ED (2017) Cellular and molecular mechanisms of neuroprotection and plasticity after traumatic brain injury. Neurochem Int 111:1–2. https://doi.org/10.1016/j.neuint.2017.09.014

    Article  CAS  PubMed  Google Scholar 

  43. Corps KN, Roth TL, McGavern DB (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72(3):355–362. https://doi.org/10.1001/jamaneurol.2014.3558

    Article  PubMed  PubMed Central  Google Scholar 

  44. Oyinbo CA (2011) Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp 71(2):281–299

    Google Scholar 

  45. Shultz RB, Zhong Y (2017) Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res 12(5):702–713. https://doi.org/10.4103/1673-5374.206633

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dobkin BH (2009) Motor rehabilitation after stroke, traumatic brain, and spinal cord injury: common denominators within recent clinical trials. Curr Opin Neurol 22(6):563–569. https://doi.org/10.1097/WCO.0b013e3283314b11

    Article  PubMed  PubMed Central  Google Scholar 

  47. Steadman-Pare D, Colantonio A, Ratcliff G, Chase S, Vernich L (2001) Factors associated with perceived quality of life many years after traumatic brain injury. J Head Trauma Rehabil 16(4):330–342

    Article  CAS  PubMed  Google Scholar 

  48. Nichols-Larsen DS, Clark PC, Zeringue A, Greenspan A, Blanton S (2005) Factors influencing stroke survivors’ quality of life during subacute recovery. Stroke 36(7):1480–1484. https://doi.org/10.1161/01.STR.0000170706.13595.4f

    Article  PubMed  Google Scholar 

  49. Juengst SB, Adams LM, Bogner JA, Arenth PM, O’Neil-Pirozzi TM, Dreer LE, Hart T, Bergquist TF et al (2015) Trajectories of life satisfaction after traumatic brain injury: influence of life roles, age, cognitive disability, and depressive symptoms. Rehabil Psychol 60(4):353–364. https://doi.org/10.1037/rep0000056

    Article  PubMed  PubMed Central  Google Scholar 

  50. Diaz AP, Schwarzbold ML, Thais ME, Cavallazzi GG, Schmoeller R, Nunes JC, Hohl A, Guarnieri R et al (2014) Personality changes and return to work after severe traumatic brain injury: a prospective study. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) 36(3):213–219

    Article  Google Scholar 

  51. Eriks-Hoogland I, de Groot S, Snoek G, Stucki G, Post M, van der Woude L (2016) Association of shoulder problems in persons with spinal cord injury at discharge from inpatient rehabilitation with activities and participation 5 years later. Arch Phys Med Rehabil 97(1):84–91. https://doi.org/10.1016/j.apmr.2015.08.432

    Article  PubMed  Google Scholar 

  52. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345. https://doi.org/10.1038/nbt.1807

    Article  CAS  PubMed  Google Scholar 

  53. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200(4):373–383. https://doi.org/10.1083/jcb.201211138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fruhbeis C, Frohlich D, Kramer-Albers EM (2012) Emerging roles of exosomes in neuron-glia communication. Front Physiol 3:119. https://doi.org/10.3389/fphys.2012.00119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Benussi L, Ciani M, Tonoli E, Morbin M, Palamara L, Albani D, Fusco F, Forloni G et al (2016) Loss of exosomes in progranulin-associated frontotemporal dementia. Neurobiol Aging 40:41–49. https://doi.org/10.1016/j.neurobiolaging.2016.01.001

    Article  CAS  PubMed  Google Scholar 

  56. Tunesi M, Fusco F, Fiordaliso F, Corbelli A, Biella G, Raimondi MT (2016) Optimization of a 3D dynamic culturing system for in vitro modeling of frontotemporal neurodegeneration-relevant pathologic features. Front Aging Neurosci 8:146. https://doi.org/10.3389/fnagi.2016.00146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Musunuri S, Khoonsari PE, Mikus M, Wetterhall M, Haggmark-Manberg A, Lannfelt L, Erlandsson A, Bergquist J et al (2016) Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain. J Alzheimer's Dis 54(4):1671–1686. https://doi.org/10.3233/jad-160271

    Article  CAS  Google Scholar 

  58. Fernandes HJ, Hartfield EM, Christian HC, Emmanoulidou E, Zheng Y, Booth H, Bogetofte H, Lang C et al (2016) ER stress and autophagic perturbations lead to elevated extracellular alpha-synuclein in GBA-N370S Parkinson's iPSC-derived dopamine neurons. Stem Cell Rep 6(3):342–356. https://doi.org/10.1016/j.stemcr.2016.01.013

    Article  CAS  Google Scholar 

  59. Song P, Trajkovic K, Tsunemi T, Krainc D (2016) Parkin modulates endosomal organization and function of the endo-lysosomal pathway. J Neurosci 36(8):2425–2437. https://doi.org/10.1523/jneurosci.2569-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fraser KB, Rawlins AB, Clark RG, Alcalay RN, Standaert DG, Liu N, West AB (2016) Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov Disord 31(10):1543–1550. https://doi.org/10.1002/mds.26686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zondler L, Feiler MS, Freischmidt A, Ruf WP, Ludolph AC, Danzer KM, Weishaupt JH (2016) Impaired activation of ALS monocytes by exosomes. Immunol Cell Biol 95:207–214. https://doi.org/10.1038/icb.2016.89

    Article  CAS  PubMed  Google Scholar 

  62. Lee M, Ban JJ, Kim KY, Jeon GS, Im W, Sung JJ, Kim M (2016) Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro. Biochem Biophys Res Commun 479(3):434–439. https://doi.org/10.1016/j.bbrc.2016.09.069

    Article  CAS  PubMed  Google Scholar 

  63. Westergard T, Jensen BK, Wen X, Cai J, Kropf E, Iacovitti L, Pasinelli P, Trotti D (2016) Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep 17(3):645–652. https://doi.org/10.1016/j.celrep.2016.09.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang X, Abels ER, Redzic JS, Margulis J, Finkbeiner S, Breakefield XO (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):459–470. https://doi.org/10.1007/s10571-016-0350-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lee M, Liu T, Im W, Kim M (2016) Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington’s disease in vitro model. Eur J Neurosci 44(4):2114–2119. https://doi.org/10.1111/ejn.13275

    Article  PubMed  Google Scholar 

  66. Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, Sapp E, Ly S et al (2016) Exosome-mediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing. Mol Ther 24:1836–1847. https://doi.org/10.1038/mt.2016.126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sapan HB, Paturusi I, Islam AA, Yusuf I, Patellongi I, Massi MN, Pusponegoro AD, Arief SK et al (2017) Interleukin-6 and interleukin-10 plasma levels and mRNA expression in polytrauma patients. Chin J Traumatol Zhonghua Chuang Shang Za Zhi 20(6):318–322. https://doi.org/10.1016/j.cjtee.2017.05.003

    Article  PubMed  Google Scholar 

  68. Cwikiel J, Seljeflot I, Berge E, Njerve IU, Ulsaker H, Arnesen H, Flaa A (2018) Effect of strenuous exercise on mediators of inflammation in patients with coronary artery disease. Cytokine 105:17–22. https://doi.org/10.1016/j.cyto.2018.02.006

    Article  CAS  PubMed  Google Scholar 

  69. Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J et al (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289(7):3869–3875. https://doi.org/10.1074/jbc.C113.532267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kalluri R, LeBleu VS (2016) Discovery of double-stranded genomic DNA in circulating exosomes. Cold Spring Harb Symp Quant Biol 81:275–280. https://doi.org/10.1101/sqb.2016.81.030932

    Article  PubMed  Google Scholar 

  71. Organization WH (2007) Neurological disorders: public health challenges. WHO Press, Switzerland

    Google Scholar 

  72. Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC (2007) The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 22(5):341–353

    PubMed  Google Scholar 

  73. Faul M, Xu L, Wald MM, Coronado VG (2010) Traumatic brain injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006

  74. Taylor CA, Bell J, Breiding MJ, Xu L (2017) Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013. MMWR Surveill Summ 66(9):1–16. https://doi.org/10.15585/mmwr.ss6609a1

    Article  PubMed  PubMed Central  Google Scholar 

  75. Humphreys I, Wood RL, Phillips CJ, Macey S (2013) The costs of traumatic brain injury: a literature review. ClinicoEcon Outcomes Res 5:281–287. https://doi.org/10.2147/ceor.s44625

    Article  PubMed  PubMed Central  Google Scholar 

  76. Corrigan JD, Selassie AW, Orman JA (2010) The epidemiology of traumatic brain injury. J Head Trauma Rehabil 25(2):72–80. https://doi.org/10.1097/HTR.0b013e3181ccc8b4

    Article  PubMed  Google Scholar 

  77. Singh A, Tetreault L, Kalsi-Ryan S, Nouri A, Fehlings MG (2014) Global prevalence and incidence of traumatic spinal cord injury. Clin Epidemiol 6:309–331. https://doi.org/10.2147/CLEP.S68889

    Article  PubMed  PubMed Central  Google Scholar 

  78. Moons WG, Shields GS (2015) Anxiety, not anger, induces inflammatory activity: an avoidance/approach model of immune system activation. Emotion 15(4):463–476. https://doi.org/10.1037/emo0000055

    Article  PubMed  Google Scholar 

  79. Spinal Cord Injury (SCI) Facts and Figures at a Glance (2016) National Spinal Cord Injury Statistical Center

  80. McDonald JW, Sdowsky C (2002) Spinal-cord injury. Lancet 359(9304):417–425

    Article  PubMed  Google Scholar 

  81. van Middendorp JJ, Goss B, Urquhart S, Atresh S, Williams RP, Schuetz M (2011) Diagnosis and prognosis of traumatic spinal cord injury. Glob Spine J 1(1):1–8. https://doi.org/10.1055/s-0031-1296049

    Article  Google Scholar 

  82. Sezer N, Akkus S, Ugurlu FG (2015) Chronic complications of spinal cord injury. World J Orthop 6(1):24–33. https://doi.org/10.5312/wjo.v6.i1.24

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hossmann KA (2006) Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 26(7–8):1057–1083. https://doi.org/10.1007/s10571-006-9008-1

    Article  PubMed  Google Scholar 

  84. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S et al (2016) Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 133(4):447–454. https://doi.org/10.1161/cir.0000000000000366

    Article  PubMed  Google Scholar 

  85. Skolarus LE, Burke JF, Brown DL, Freedman VA (2014) Understanding stroke survivorship: expanding the concept of poststroke disability. Stroke 45(1):224–230. https://doi.org/10.1161/strokeaha.113.002874

    Article  PubMed  Google Scholar 

  86. Mayo NE, Aburub A, Brouillette MJ, Kuspinar A, Moriello C, Rodriguez AM, Scott S (2016) In support of an individualized approach to assessing quality of life: comparison between Patient Generated Index and standardized measures across four health conditions. Qual Life Res 26:601–609. https://doi.org/10.1007/s11136-016-1480-6

    Article  PubMed  Google Scholar 

  87. Aronowski J, Zhao X (2011) Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42(6):1781–1786. https://doi.org/10.1161/strokeaha.110.596718

    Article  PubMed  PubMed Central  Google Scholar 

  88. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M et al (2008) Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117(4):e25–e146. https://doi.org/10.1161/circulationaha.107.187998

  89. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24(1):35–41

    Article  PubMed  Google Scholar 

  90. George PM, Steinberg GK (2015) Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87(2):297–309. https://doi.org/10.1016/j.neuron.2015.05.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kirshner HS (2009) Differentiating ischemic stroke subtypes: risk factors and secondary prevention. J Neurol Sci 279(1–2):1–8. https://doi.org/10.1016/j.jns.2008.12.012

    Article  PubMed  Google Scholar 

  92. Bell JD, Park E, Ai J, Baker AJ (2009) PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma. Cell Death Differ 16(12):1665–1680. https://doi.org/10.1038/cdd.2009.106

    Article  CAS  PubMed  Google Scholar 

  93. Liu Y, Wang L, Long ZY, Wu YM, Wan Q, Jiang JX, Wang ZG (2013) Inhibiting PTEN protects hippocampal neurons against stretch injury by decreasing membrane translocation of AMPA receptor GluR2 subunit. PLoS One 8(6):e65431. https://doi.org/10.1371/journal.pone.0065431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM et al (2017) Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318(4):360–370. https://doi.org/10.1001/jama.2017.8334

    Article  PubMed  PubMed Central  Google Scholar 

  95. Stern RA, Tripodis Y, Baugh CM, Fritts NG, Martin BM, Chaisson C, Cantu RC, Joyce JA et al (2016) Preliminary study of plasma exosomal tau as a potential biomarker for chronic traumatic encephalopathy. J Alzheimer's Dis 51(4):1099–1109. https://doi.org/10.3233/jad-151028

    Article  CAS  Google Scholar 

  96. Taylor DD, Gercel-Taylor C (2014) Exosome platform for diagnosis and monitoring of traumatic brain injury. Philos Trans R Soc Lond Ser B Biol Sci 369(1652):20130503. https://doi.org/10.1098/rstb.2013.0503

    Article  CAS  Google Scholar 

  97. Raheja A, Sinha S, Samson N, Bhoi S, Subramanian A, Sharma P, Sharma BS (2016) Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial. J Neurosurg 125(3):631–641. https://doi.org/10.3171/2015.6.JNS15674

    Article  CAS  PubMed  Google Scholar 

  98. Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, Zhou ML, Zhu L et al (2013) Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res 38(10):2072–2083. https://doi.org/10.1007/s11064-013-1115-z

    Article  CAS  PubMed  Google Scholar 

  99. Intiso D, Zarrelli MM, Lagioia G, Di Rienzo F, Checchia De Ambrosio C, Simone P, Tonali P, Cioffi Dagger RP (2004) Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients. Neurol Sci 24(6):390–396. https://doi.org/10.1007/s10072-003-0194-z

    Article  CAS  PubMed  Google Scholar 

  100. Tuttolomondo A, Di Raimondo D, Pecoraro R, Serio A, D'Aguanno G, Pinto A, Licata G (2010) Immune-inflammatory markers and arterial stiffness indexes in subjects with acute ischemic stroke. Atherosclerosis 213(1):311–318. https://doi.org/10.1016/j.atherosclerosis.2010.08.065

    Article  CAS  PubMed  Google Scholar 

  101. Rodriguez-Yanez M, Sobrino T, Arias S, Vazquez-Herrero F, Brea D, Blanco M, Leira R, Castellanos M et al (2011) Early biomarkers of clinical-diffusion mismatch in acute ischemic stroke. Stroke 42(10):2813–2818. https://doi.org/10.1161/strokeaha.111.614503

    Article  CAS  PubMed  Google Scholar 

  102. Su JA, Chou SY, Tsai CS, Hung TH (2012) Cytokine changes in the pathophysiology of poststroke depression. Gen Hosp Psychiatry 34(1):35–39. https://doi.org/10.1016/j.genhosppsych.2011.09.020

    Article  PubMed  Google Scholar 

  103. Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276(1):13–26. https://doi.org/10.1111/j.1742-4658.2008.06766.x

    Article  CAS  PubMed  Google Scholar 

  104. Fann DY, Lee SY, Manzanero S, Chunduri P, Sobey CG, Arumugam TV (2013) Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev 12(4):941–966. https://doi.org/10.1016/j.arr.2013.09.004

    Article  CAS  PubMed  Google Scholar 

  105. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW (2012) Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg 117(6):1119–1125. https://doi.org/10.3171/2012.9.JNS12815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kwon BK, Stammers AM, Belanger LM, Bernardo A, Chan D, Bishop CM, Slobogean GP, Zhang H et al (2010) Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J Neurotrauma 27(4):669–682. https://doi.org/10.1089/neu.2009.1080

    Article  PubMed  Google Scholar 

  107. Lejbman N, Olivera A, Heinzelmann M, Feng R, Yun S, Kim HS, Gill J (2016) Active duty service members who sustain a traumatic brain injury have chronically elevated peripheral concentrations of Abeta40 and lower ratios of Abeta42/40. Brain Inj 30(12):1436–1441. https://doi.org/10.1080/02699052.2016.1219054

    Article  PubMed  PubMed Central  Google Scholar 

  108. Bogoslovsky T, Wilson D, Chen Y, Hanlon D, Gill J, Jeromin A, Song L, Moore C et al (2017) Increases of plasma levels of glial fibrillary acidic protein, tau, and amyloid beta up to 90 days after traumatic brain injury. J Neurotrauma 34(1):66–73. https://doi.org/10.1089/neu.2015.4333

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kaerst L, Kuhlmann A, Wedekind D, Stoeck K, Lange P, Zerr I (2013) Cerebrospinal fluid biomarkers in Alzheimer’s disease, vascular dementia and ischemic stroke patients: a critical analysis. J Neurol 260(11):2722–2727. https://doi.org/10.1007/s00415-013-7047-3

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K (2001) Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 297(3):187–190

    Article  CAS  PubMed  Google Scholar 

  111. Wunderlich MT, Lins H, Skalej M, Wallesch CW, Goertler M (2006) Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clin Neurol Neurosurg 108(6):558–563. https://doi.org/10.1016/j.clineuro.2005.12.006

    Article  PubMed  Google Scholar 

  112. Kobayashi S, Sasaki T, Katayama T, Hasegawa T, Nagano A, Sato K (2010) Temporal-spatial expression of presenilin 1 and the production of amyloid-beta after acute spinal cord injury in adult rat. Neurochem Int 56(3):387–393. https://doi.org/10.1016/j.neuint.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  113. Wahlgren J, De LKT, Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, Valadi H (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40(17):e130. https://doi.org/10.1093/nar/gks463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cardoso AM, Guedes JR, Cardoso AL, Morais C, Cunha P, Viegas AT, Costa R, Jurado A et al (2016) Recent trends in nanotechnology toward CNS diseases: lipid-based nanoparticles and exosomes for targeted therapeutic delivery. Int Rev Neurobiol 130:1–40. https://doi.org/10.1016/bs.irn.2016.05.002

    Article  CAS  PubMed  Google Scholar 

  115. Luarte A, Batiz LF, Wyneken U, Lafourcade C (2016) Potential therapies by stem cell-derived exosomes in CNS diseases: focusing on the neurogenic niche. Stem Cells Int 2016:5736059. https://doi.org/10.1155/2016/5736059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Fais S, O’Driscoll L, Borras FE, Buzas E, Camussi G, Cappello F, Carvalho J, Cordeiro da Silva A et al (2016) Evidence-based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 10(4):3886–3899. https://doi.org/10.1021/acsnano.5b08015

    Article  CAS  PubMed  Google Scholar 

  117. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J et al (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19(10):1769–1779. https://doi.org/10.1038/mt.2011.164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. ELA S, Mager I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12(5):347–357. https://doi.org/10.1038/nrd3978

    Article  CAS  Google Scholar 

  119. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, Capelli C, Introna M et al (2013) Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev 22(5):772–780. https://doi.org/10.1089/scd.2012.0266

    Article  CAS  PubMed  Google Scholar 

  120. Zhou J, Ghoroghi S, Benito-Martin A, Wu H, Unachukwu UJ, Einbond LS, Guariglia S, Peinado H et al (2016) Characterization of induced pluripotent stem cell microvesicle genesis, morphology and pluripotent content. Sci Rep 6:19743. https://doi.org/10.1038/srep19743

  121. Chopp M, Zhang ZG (2015) Emerging potential of exosomes and noncoding microRNAs for the treatment of neurological injury/diseases. Expert Opin Emerging Drugs 20(4):523–526. https://doi.org/10.1517/14728214.2015.1061993

    Article  CAS  Google Scholar 

  122. Patterson M, Gaeta X, Loo K, Edwards M, Smale S, Cinkornpumin J, Xie Y, Listgarten J et al (2014) Let-7 miRNAs can act through notch to regulate human gliogenesis. Stem Cell Rep 3(5):758–773. https://doi.org/10.1016/j.stemcr.2014.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Coolen M, Katz S, Bally-Cuif L (2013) miR-9: a versatile regulator of neurogenesis. Front Cell Neurosci 7:220. https://doi.org/10.3389/fncel.2013.00220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Liu XS, Chopp M, Zhang RL, Tao T, Wang XL, Kassis H, Hozeska-Solgot A, Zhang L et al (2011) MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6(8):e23461. https://doi.org/10.1371/journal.pone.0023461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mercier F, Hatton GI (2001) Connexin 26 and basic fibroblast growth factor are expressed primarily in the subpial and subependymal layers in adult brain parenchyma: roles in stem cell proliferation and morphological plasticity? J Comp Neurol 431(1):88–104

    Article  CAS  PubMed  Google Scholar 

  126. Aguirre A, Rubio ME, Gallo V (2010) Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467(7313):323–327. https://doi.org/10.1038/nature09347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang Z, Yan R, Zhang Q, Li J, Kang X, Wang H, Huan L, Zhang L et al (2014) Hes1, a Notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury. Brain Res 1583:65–78. https://doi.org/10.1016/j.brainres.2014.07.037

    Article  CAS  PubMed  Google Scholar 

  128. Chiquet-Ehrismann R, Orend G, Chiquet M, Tucker RP, Midwood KS (2014) Tenascins in stem cell niches. Matrix Biol 37:112–123. https://doi.org/10.1016/j.matbio.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  129. Zhuang X, Teng Y, Samykutty A, Mu J, Deng Z, Zhang L, Cao P, Rong Y et al (2016) Grapefruit-derived nanovectors delivering therapeutic miR17 through an intranasal route inhibit brain tumor progression. Mol Ther 24(1):96–105. https://doi.org/10.1038/mt.2015.188

    Article  CAS  PubMed  Google Scholar 

  130. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A et al (2015) Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release 207:18–30. https://doi.org/10.1016/j.jconrel.2015.03.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cooper JM, Wiklander PB, Nordin JZ, Al-Shawi R, Wood MJ, Vithlani M, Schapira AH, Simons JP et al (2014) Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord 29(12):1476–1485. https://doi.org/10.1002/mds.25978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T et al (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21(1):185–191. https://doi.org/10.1038/mt.2012.180

    Article  CAS  PubMed  Google Scholar 

  133. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (2013) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33(11):1711–1715. https://doi.org/10.1038/jcbfm.2013.152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Pusic KM, Pusic AD, Kraig RP (2016) Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell Mol Neurobiol 36(3):313–325. https://doi.org/10.1007/s10571-015-0269-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Institutes of Health Intramural Department of Research.

Author information

Authors and Affiliations

  1. National Institutes of Health, National Institute of Nursing Research, 1 Cloister Ct, Bethesda, MD, 20814, USA

    Nicole Osier, Vida Motamedi, Katie Edwards & Jessica Gill

  2. University of Texas at Austin, Austin, TX, USA

    Nicole Osier

  3. Healthcare Genetics Doctoral Program, Clemson University School of Nursing, 508 Edwards, Clemson, SC, 29631, USA

    Katie Edwards

  4. Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Suite B-400, Pittsburgh, PA, 15213, USA

    Ava Puccio

  5. University of Pennsylvania School of Medicine, Suite 205 Medical Office Building, 51 N 39TH ST, Philadelphia, PA, 19104, USA

    Ramon Diaz-Arrastia

  6. National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Building 51, Room 2306, 4860 South Palmer Road, Bethesda, MD, 20889-5649, USA

    Kimbra Kenney

Authors
  1. Nicole Osier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vida Motamedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katie Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ava Puccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramon Diaz-Arrastia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kimbra Kenney
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jessica Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicole Osier.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Osier, N., Motamedi, V., Edwards, K. et al. Exosomes in Acquired Neurological Disorders: New Insights into Pathophysiology and Treatment. Mol Neurobiol 55, 9280–9293 (2018). https://doi.org/10.1007/s12035-018-1054-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1054-4

Keywords

Search

Navigation