Focus on extracellular vesicles: Exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and Parkinson’s disease

International Journal of Molecular Sciences

Volumn 17, Issue 2, 2016, Pages

  Vella, Laura J ^a   Hill, Andrew F ^b   Cheng, Lesley ^b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b LA TROBE UNIVERSITY   (Australia)

Author keywords

Alzheimer s disease; Biomarkers; Exosomes; Extracellular vesicles; Neurodegeneration; Parkinson s disease; Protein misfolding; Protein trafficking

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E; BAFILOMYCIN; BETA SECRETASE; BIOLOGICAL MARKER; CD11B ANTIGEN; CD45 ANTIGEN; DJ 1 PROTEIN; GAMMA SECRETASE; LEUCINE RICH REPEAT KINASE 2; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 1; MICRORNA; NERVE CELL ADHESION MOLECULE; NERVE CELL ADHESION MOLECULE L1; NOTCH3 RECEPTOR; PRION PROTEIN; RAPAMYCIN; ROTENONE; SYNAPTOBREVIN 2; TAU PROTEIN;

ALZHEIMER DISEASE; BRAIN CELL; COGNITION; COGNITIVE DEFECT; CONFORMATIONAL TRANSITION; ENDOPLASMIC RETICULUM; EXOSOME; HUMAN; LEWY BODY; LYSOSOME; MICROGLIA; NERVE CELL PLASTICITY; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; PROTEIN SYNTHESIS REGULATION; PROTEOMICS; REVIEW; SIGNAL TRANSDUCTION; SUBSTANTIA NIGRA PARS COMPACTA; TRANS GOLGI NETWORK; ANIMAL; CHEMISTRY; METABOLISM; PROTEIN FOLDING; PROTEIN TRANSPORT;

ALPHA-SYNUCLEIN; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BIOMARKERS; EXOSOMES; EXTRACELLULAR VESICLES; HUMANS; PARKINSON DISEASE; PROTEIN FOLDING; PROTEIN TRANSPORT;

EID: 84957584941     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17020173     Document Type: Review

References (131)

1. Braak, H.; del Tredici, K.; Rub, U.; de vos, R.A.; Jansen Steur, E.N.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 2003, 24, 197-211.
2. Braak, H.; Braak, E. Neuropathological stageing of alzheimer-related changes. Acta Neuropathol. 1991, 82, 239-259.
3. Coleman, B.M.; Hill, A.F. Extracellular vesicles—Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin. Cell Dev. Biol. 2015, 40, 89-96.
4. Russo, I.; Bubacco, L.; Greggio, E. Exosomes-associated neurodegeneration and progression of Parkinson’s disease. Am. J. Neurodegener. Dis. 2012, 1, 217-225.
5. Kalra, H.; Drummen, G.P.C.; Mathivanan, S. Focus on extracellular vesicles: An introduction to the next small big thing. Int. J. Mol. Sci. 2016, 17, doi:10.3390/ijms17020170.
6. Frohlich, D.; Kuo, W.P.; Fruhbeis, C.; Sun, J.J.; Zehendner, C.M.; Luhmann, H.J.; Pinto, S.; Toedling, J.; Trotter, J.; Kramer-Albers, E.M. 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. 2014, 369, doi:10.1098/rstb.2013.0510.
7. Fruhbeis, C.; Frohlich, D.; Kuo, W.P.; Kramer-Albers, E.M. Extracellular vesicles as mediators of neuron-glia communication. Front. Cell. Neurosci. 2013, 7, doi:10.3389/fncel.2013.00182.
8. Skog, J.; Wurdinger, T.; van Rijn, S.; Meijer, D.H.; Gainche, L.; Sena-Esteves, M.; Curry, W.T.; Carter, B.S.; Krichevsky, A.M.; Breakefield, X.O. Glioblastoma microvesicles transport rna and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 2008, 10, 1470-1476.
9. Bronisz, A.; Wang, Y.; Nowicki, M.O.; Peruzzi, P.; Ansari, K.I.; Ogawa, D.; Balaj, L.; de Rienzo, G.; Mineo, M.; Nakano, I.; et al. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res. 2014, 74, 738-750.
10. Rajendran, L.; Bali, J.; Barr, M.M.; Court, F.A.; Kramer-Albers, E.M.; Picou, F.; Raposo, G.; van der vos, K.E.; van Niel, G.; Wang, J.; et al. Emerging roles of extracellular vesicles in the nervous system. J. Neurosci. 2014, 34, 15482-15489.
11. Vingtdeux, V.; Sergeant, N.; Buee, L. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front. Physiol. 2012, 3, doi:10.3389/fphys.2012.00229.
12. Bellingham, S.A.; Guo, B.B.; Coleman, B.M.; Hill, A.F. Exosomes: Vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front. Physiol. 2012, 3, doi:org/10.3389/fphys.2012.00124.
13. Villemagne, V.L.; Burnham, S.; Bourgeat, P.; Brown, B.; Ellis, K.A.; Salvado, O.; Szoeke, C.; Macaulay, S.L.; Martins, R.; Maruff, P.; et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: A prospective cohort study. Lancet Neurol. 2013, 12, 357-367.
14. Cataldo, A.M.; Petanceska, S.; Terio, N.B.; Peterhoff, C.M.; Durham, R.; Mercken, M.; Mehta, P.D.; Buxbaum, J.; Haroutunian, V.; Nixon, R.A. Aβ localization in abnormal endosomes: Association with earliest Aβ elevations in ad and down syndrome. Neurobiol. Aging 2004, 25, 1263-1272.
15. Hartmann, T.; Bieger, S.C.; Bruhl, B.; Tienari, P.J.; Ida, N.; Allsop, D.; Roberts, G.W.; Masters, C.L.; Dotti, C.G.; Unsicker, K.; et al. Distinct sites of intracellular production for Alzheimer’s disease Aβ40/42 amyloid peptides. Nat. Med. 1997, 3, 1016-1020.
16. Jucker, M.; Walker, L.C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013, 501, 45-51.
17. Caporaso, G.L.; Takei, K.; Gandy, S.E.; Matteoli, M.; Mundigl, O.; Greengard, P.; de Camilli P. Morphologic and biochemical analysis of the intracellular trafficking of the Alzheimer β/A4 amyloid precursor protein. J. Neurosci. 1994, 14, 3122-3138.
18. Tam, J.H.; Seah, C.; Pasternak, S.H. The Amyloid Precursor Protein is rapidly transported from the Golgi apparatus to the lysosome and where it is processed into β-amyloid. Mol. Brain 2014, 7, doi:10.1186/s13041-014-0054-1.
19. Hu, X.; Crick, S.L.; Bu, G.; Frieden, C.; Pappu, R.V.; Lee, J.M. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-β peptide. Proc. Natl. Acad. Sci. USA 2009, 106, 20324-20329.
20. Keller, J.N.; Hanni, K.B.; Markesbery, W.R. Impaired proteasome function in Alzheimer’s disease. J. Neurochem. 2000, 75, 436-439.
21. Rajendran, L.; Honsho, M.; Zahn, T.R.; Keller, P.; Geiger, K.D.; Verkade, P.; Simons, K. Alzheimer’s disease β-amyloid peptides are released in association with exosomes. Proc. Natl. Acad. Sci. USA 2006, 103, 11172-11177.
22. Vingtdeux, V.; Hamdane, M.; Loyens, A.; Gele, P.; Drobeck, H.; Begard, S.; Galas, M.C.; Delacourte, A.; Beauvillain, J.C.; Buee, L.; et al. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 2007, 282, 18197-18205.
23. Sharples, R.A.; Vella, L.J.; Nisbet, R.M.; Naylor, R.; Perez, K.; Barnham, K.J.; Masters, C.L.; Hill, A.F. Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J. 2008, 22, 1469-1478.
24. Bulloj, A.; Leal, M.C.; Xu, H.; Castano, E.M.; Morelli, L. Insulin-degrading enzyme sorting in exosomes: A secretory pathway for a key brain amyloid-β degrading protease. J. Alzheimer’s Dis. 2010, 19, 79-95.
25. An, K.; Klyubin, I.; Kim, Y.; Jung, J.H.; Mably, A.J.; O’Dowd, S.T.; Lynch, T.; Kanmert, D.; Lemere, C.A.; Finan, G.M., et al. Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo. Mol. Brain 2013, 6, 47.
26. Yuyama, K.; Sun, H.; Mitsutake, S.; Igarashi, Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J. Biol. Chem. 2012, 287, 10977-10989.
27. Wang, G.; Dinkins, M.; He, Q.; Zhu, G.; Poirier, C.; Campbell, A.; Mayer-Proschel, M.; Bieberich, E. Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): Potential mechanism of apoptosis induction in alzheimer disease (AD). J. Biol. Chem. 2012, 287, 21384-21395.
28. Dinkins, M.B.; Dasgupta, S.; Wang, G.; Zhu, G.; Bieberich, E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol. Aging 2014, 35, 1792-1800.
29. Saman, S.; Kim, W.; Raya, M.; Visnick, Y.; Miro, S.; Saman, S.; Jackson, B.; McKee, A.C.; Alvarez, V.E.; Lee, N.C.; et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 2012, 287, 3842-3849.
30. Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011, 29, 341-345.
31. Perez-Gonzalez, R.; Gauthier, S.A.; Kumar, A.; Levy, E. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J. Biol. Chem. 2012, 287, 43108-43115.
32. Yuyama, K.; Sun, H.; Sakai, S.; Mitsutake, S.; Okada, M.; Tahara, H.; Furukawa, J.; Fujitani, N.; Shinohara, Y.; Igarashi, Y. Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 2014, 289, 24488-24498.
33. Yuyama, K.; Sun, H.; Usuki, S.; Sakai, S.; Hanamatsu, H.; Mioka, T.; Kimura, N.; Okada, M.; Tahara, H.; Furukawa, J., et al. A potential function for neuronal exosomes: Sequestering intracerebral amyloid-β peptide. FEBS Lett. 2015, 589, 84-88.
34. Dinkins, M.B.; Dasgupta, S.; Wang, G.; Zhu, G.; He, Q.; Kong, J.N.; Bieberich, E. The 5XFAD mouse model of Alzheimer’s disease exhibits an age-dependent increase in anti-ceramide IGG and exogenous administration of ceramide further increases anti-ceramide titers and amyloid plaque burden. J. Alzheimer’s Dis. 2015, 46, 55-61.
35. Fiandaca, M.S.; Kapogiannis, D.; Mapstone, M.; Boxer, A.; Eitan, E.; Schwartz, J.B.; Abner, E.L.; Petersen, R.C.; Federoff, H.J.; Miller, B.L., et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimer’s Dement. 2014, 11, 600-607.
36. Banigan, M.G.; Kao, P.F.; Kozubek, J.A.; Winslow, A.R.; Medina, J.; Costa, J.; Schmitt, A.; Schneider, A.; Cabral, H.; Cagsal-Getkin, O., et al. Differential expression of exosomal micrornas in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS ONE 2013, 8, e48814.
37. Pituch, K.C.; Moyano, A.L.; Lopez-Rosas, A.; Marottoli, F.M.; Li, G.; Hu, C.; van Breemen, R.; Mansson, J.E.; Givogri, M.I. Dysfunction of platelet-derived growth factor receptor α (PDGFRα) represses the production of oligodendrocytes from arylsulfatase A-deficient multipotential neural precursor cells. J. Biol. Chem. 2015, 290, 7040-7053.
38. Yelamanchili, S.V.; Lamberty, B.G.; Rennard, D.A.; Morsey, B.M.; Hochfelder, C.G.; Meays, B.M.; Levy, E.; Fox, H.S. miR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in siv neurological disease. PLoS Pathog. 2015, 11, e1005032.
39. Lotvall, J.; Hill, A.F.; Hochberg, F.; Buzas, E.I.; di Vizio, D.; Gardiner, C.; Gho, Y.S.; Kurochkin, I.V.; Mathivanan, S.; Quesenberry, P., et al. 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, doi:10.3402/jev.v3.26913.
40. Joshi, P.; Benussi, L.; Furlan, R.; Ghidoni, R.; Verderio, C. Extracellular vesicles in Alzheimer’s disease: Friends or foes? Focus on Aβ-vesicle interaction. Int. J. Mol. Sci. 2015, 16, 4800-4813.
41. Fitzner, D.; Schnaars, M.; van Rossum, D.; Krishnamoorthy, G.; Dibaj, P.; Bakhti, M.; Regen, T.; Hanisch, U.K.; Simons, M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J. Cell Sci. 2011, 124, 447-458.
42. Nixon, R.A.; Wegiel, J.; Kumar, A.; Yu, W.H.; Peterhoff, C.; Cataldo, A.; Cuervo, A.M. Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 2005, 64, 113-122.
43. Nilsson, P.; Loganathan, K.; Sekiguchi, M.; Matsuba, Y.; Hui, K.; Tsubuki, S.; Tanaka, M.; Iwata, N.; Saito, T.; Saido, T.C. Aβ secretion and plaque formation depend on autophagy. Cell Rep. 2013, 5, 61-69.
44. Yu, W.H.; Cuervo, A.M.; Kumar, A.; Peterhoff, C.M.; Schmidt, S.D.; Lee, J.H.; Mohan, P.S.; Mercken, M.; Farmery, M.R.; Tjernberg, L.O., et al. Macroautophagy—A novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 2005, 171, 87-98.
45. Fader, C.M.; Sanchez, D.; Furlan, M.; Colombo, M.I. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic (Cph. Den.) 2008, 9, 230-250.
46. Caccamo, A.; Majumder, S.; Richardson, A.; Strong, R.; Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and tau: Effects on cognitive impairments. J. Biol. Chem. 2010, 285, 13107-13120.
47. Frost, B.; Jacks, R.L.; Diamond, M.I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 2009, 284, 12845-12852.
48. Chai, X., Dage, J.L., Citron, M. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol. Dis. 2012, 48, 356-366.
49. Simon, D.; Garcia-Garcia, E.; Royo, F.; Falcon-Perez, J.M.; Avila, J. Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett. 2012, 586, 47-54.
50. Borghi, R.; Marchese, R.; Negro, A.; Marinelli, L.; Forloni, G.; Zaccheo, D.; Abbruzzese, G.; Tabaton, M. Full length α-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci. Lett. 2000, 287, 65-67.
51. El-Agnaf, O.M.; Salem, S.A.; Paleologou, K.E.; Cooper, L.J.; Fullwood, N.J.; Gibson, M.J.; Curran, M.D.; Court, J.A.; Mann, D.M.; Ikeda, S., et al. α-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003, 17, 1945-1947.
52. Emmanouilidou, E.; Melachroinou, K.; Roumeliotis, T.; Garbis, S.D.; Ntzouni, M.; Margaritis, L.H.; Stefanis, L.; Vekrellis, K. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 2010, 30, 6838-6851.
53. Danzer, K.M.; Kranich, L.R.; Ruf, W.P.; Cagsal-Getkin, O.; Winslow, A.R.; Zhu, L.; Vanderburg, C.R.; McLean, P.J. Exosomal cell-to-cell transmission of α synuclein oligomers. Mol. Neurodegener. 2012, 7, doi:10.1186/1750-1326-7-42.
54. Alvarez-Erviti, L.; Seow, Y.; Schapira, A.H.; Gardiner, C.; Sargent, I.L.; Wood, M.J.; Cooper, J.M. Lysosomal dysfunction increases exosome-mediated α-synuclein release and transmission. Neurobiol. Dis. 2011, 42, 360-367.
55. Kong, S.M.; Chan, B.K.; Park, J.S.; Hill, K.J.; Aitken, J.B.; Cottle, L.; Farghaian, H.; Cole, A.R.; Lay, P.A.; Sue, C.M., et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-synuclein externalization via exosomes. Hum. Mol. Genet. 2014, 23, 2816-2833.
56. Tsunemi, T.; Hamada, K.; Krainc, D. ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J. Neurosci. 2014, 34, 15281-15287.
57. Melachroinou, K.; Xilouri, M.; Emmanouilidou, E.; Masgrau, R.; Papazafiri, P.; Stefanis, L.; Vekrellis, K. Deregulation of calcium homeostasis mediates secreted α-synuclein-induced neurotoxicity. Neurobiol. Aging 2013, 34, 2853-2865.
58. Pan-Montojo, F.; Schwarz, M.; Winkler, C.; Arnhold, M.; O’Sullivan, G.A.; Pal, A.; Said, J.; Marsico, G.; Verbavatz, J.M.; Rodrigo-Angulo, M., et al. Environmental toxins trigger PD-like progression via increased α-synuclein release from enteric neurons in mice. Sci. Rep. 2012, 2, 898.
59. Poehler, A.M.; Xiang, W.; Spitzer, P.; May, V.; Meixner, H.; Rockenstein, E.; Chutna, O.; Outeiro, T.; Winkler, J.; Masliah, E., et al. Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment. Autophagy 2014, 10, 2171-2192.
60. Shi, M.; Liu, C.; Cook, T.J.; Bullock, K.M.; Zhao, Y.; Ginghina, C.; Li, Y.; Aro, P.; Dator, R.; He, C., et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol. 2014, 128, 639-650.
61. Kunadt, M.; Eckermann, K.; Stuendl, A.; Gong, J.; Russo, B.; Strauss, K.; Rai, S.; Kugler, S.; Falomir Lockhart, L.; Schwalbe, M., et al. Extracellular vesicle sorting of α-synuclein is regulated by sumoylation. Acta Neuropathol. 2015, 129, 695-713.
62. Hasegawa, T.; Konno, M.; Baba, T.; Sugeno, N.; Kikuchi, A.; Kobayashi, M.; Miura, E.; Tanaka, N.; Tamai, K.; Furukawa, K., et al. The AAA-ATPASE VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein. PLoS ONE 2011, 6, e29460.
63. Ejlerskov, P.; Rasmussen, I.; Nielsen, T.T.; Bergstrom, A.L.; Tohyama, Y.; Jensen, P.H.; Vilhardt, F. Tubulin polymerization-promoting protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion. J. Biol. Chem. 2013, 288, 17313-17335.
64. Grathwohl, S.A.; Steiner, J.A.; Britschgi, M.; Brundin, P. Mind the gut: Secretion of α-synuclein by enteric neurons. J. Neurochem. 2013, 125, 487-490.
65. Paillusson, S.; Clairembault, T.; Biraud, M.; Neunlist, M.; Derkinderen, P. Activity-dependent secretion of α-synuclein by enteric neurons. J. Neurochem. 2013, 125, 512-517.
66. Baixauli, F.; Lopez-Otin, C.; Mittelbrunn, M. Exosomes and autophagy: Coordinated mechanisms for the maintenance of cellular fitness. Front. Immunol. 2014, 5, doi:10.3389/fimmu.2014.00403.
67. Damme, M.; Suntio, T.; Saftig, P.; Eskelinen, E.L. Autophagy in neuronal cells: General principles and physiological and pathological functions. Acta Neuropathol. 2014, 129, 337-362.
68. Betarbet, R.; Sherer, T.B.; MacKenzie, G.; Garcia-Osuna, M.; Panov, A.V.; Greenamyre, J.T. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 2000, 3, 1301-1306.
69. Wu, F.; Xu, H.D.; Guan, J.J.; Hou, Y.S.; Gu, J.H.; Zhen, X.C.; Qin, Z.H. Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease. Neuroscience 2015, 284, 900-911.
70. Fraser, K.B.; Moehle, M.S.; Daher, J.P.; Webber, P.J.; Williams, J.Y.; Stewart, C.A.; Yacoubian, T.A.; Cowell, R.M.; Dokland, T.; Ye, T., et al. LRRK2 secretion in exosomes is regulated by 14-3-3. Hum. Mol. Genet. 2013, 22, 4988-5000.
71. Ho, D.H.; Yi, S.; Seo, H.; Son, I.; Seol, W. Increased DJ-1 in urine exosome of Korean males with Parkinson’s disease. Biomed. Res. Int. 2014, 2014, 704678.
72. Follett, J.; Norwood, S.J.; Hamilton, N.A.; Mohan, M.; Kovtun, O.; Tay, S.; Zhe, Y.; Wood, S.A.; Mellick, G.D.; Silburn, P.A., et al. The VPS35 D620N mutation linked to Parkinson’s disease disrupts the cargo sorting function of retromer. Traffic 2014, 15, 230-244.
73. Van Veen, S.; Sorensen, D.M.; Holemans, T.; Holen, H.W.; Palmgren, M.G.; Vangheluwe, P. Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson’s disease and other neurological disorders. Front. Mol. Neurosci. 2014, 7, doi:10.3389/fnmol.2014.00048.
74. Ramirez, A.; Heimbach, A.; Grundemann, J.; Stiller, B.; Hampshire, D.; Cid, L.P.; Goebel, I.; Mubaidin, A.F.; Wriekat, A.L.; Roeper, J., et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 p-type atpase. Nat. Genet. 2006, 38, 1184-1191.
75. Grey, M.; Dunning, C.J.; Gaspar, R.; Grey, C.; Brundin, P.; Sparr, E.; Linse, S. Acceleration of α-synuclein aggregation by exosomes. J. Biol. Chem. 2015, 290, 2969-2982.
76. Tomlinson, P.R.; Zheng, Y.; Fischer, R.; Heidasch, R.; Gardiner, C.; Evetts, S.; Hu, M.; Wade-Martins, R.; Turner, M.R.; Morris, J., et al. Identification of distinct circulating exosomes in Parkinson’s disease. Ann. Clin. Transl. Neurol. 2015, 2, 353-361.
77. Vella, L.J.; Greenwood, D.L.; Cappai, R.; Scheerlinck, J.P.; Hill, A.F. Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. Vet. Immunol. Immunopathol. 2008, 124, 385-393.
78. Street, J.M.; Barran, P.E.; Mackay, C.L.; Weidt, S.; Balmforth, C.; Walsh, T.S.; Chalmers, R.T.; Webb, D.J.; Dear, J.W. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J. Transl. Med. 2012, 10, doi:10.1186/1479-5876-10-5.
79. Cheng, L.; Sharples, R.A.; Scicluna, B.J.; Hill, A.F. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J. Extracell. Vesicles 2014, 3, doi:10.3402/jev.v3.23743.
80. Cheng, L.; Sun, X.; Scicluna, B.J.; Coleman, B.M.; Hill, A.F. Characterization and deep sequencing analysis of exosomal and non-exosomal mirna in human urine. Kidney Int. 2013, 86, 433-444.
81. Lin, Y.T.; Cheng, J.T.; Yao, Y.C.; Juo Lo, Y.K.; Lin, C.H.; Ger, L.P.; Lu, P.J. Increased total tau but not amyloid-β(42) in cerebrospinal fluid correlates with short-term memory impairment in Alzheimer’s disease. J. Alzheimer’s Dis. 2009, 18, 907-918.
82. Parnetti, L.; Castrioto, A.; Chiasserini, D.; Persichetti, E.; Tambasco, N.; El-Agnaf, O.; Calabresi, P. Cerebrospinal fluid biomarkers in Parkinson disease. Nat. Rev. Neurol. 2013, 9, 131-140.
83. Zhou, B.; Wen, M.; Yu, W.F.; Zhang, C.L.; Jiao, L. The diagnostic and differential diagnosis utility of cerebrospinal fluid α-synuclein levels in Parkinson’s disease: A meta-analysis. Parkinson’s Dis. 2015, 2015, 567386.
84. Riemenschneider, M.; Schmolke, M.; Lautenschlager, N.; Guder, W.G.; Vanderstichele, H.; Vanmechelen, E.; Kurz, A. Cerebrospinal β-amyloid(1-42) in early Alzheimer’s disease: Association with apolipoprotein e genotype and cognitive decline. Neurosci. Lett. 2000, 284, 85-88.
85. Andreasen, N.; Hesse, C.; Davidsson, P.; Minthon, L.; Wallin, A.; Winblad, B.; Vanderstichele, H.; Vanmechelen, E.; Blennow, K. Cerebrospinal fluid β-amyloid(1-42) in Alzheimer disease: Differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch. Neurol. 1999, 56, 673-680.
86. Seeburger, J.L.; Holder, D.J.; Combrinck, M.; Joachim, C.; Laterza, O.; Tanen, M.; Dallob, A.; Chappell, D.; Snyder, K.; Flynn, M., et al. Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the optima cohort. J. Alzheimer’s Dis. 2014, 44, 525-539.
87. Chiasserini, D.; van Weering, J.R.; Piersma, S.R.; Pham, T.V.; Malekzadeh, A.; Teunissen, C.E.; de Wit, H.; Jimenez, C.R. Proteomic analysis of cerebrospinal fluid extracellular vesicles: A comprehensive dataset. J. Proteom. 2014, 106, 191-204.
88. Lopez-Font, I.; Cuchillo-Ibanez, I.; Sogorb-Esteve, A.; Garcia-Ayllon, M.S.; Saez-Valero, J. Transmembrane amyloid-related proteins in CSF as potential biomarkers for Alzheimer’s disease. Front. Neurol. 2015, 6, 125.
89. Hye, A.; Lynham, S.; Thambisetty, M.; Causevic, M.; Campbell, J.; Byers, H.L.; Hooper, C.; Rijsdijk, F.; Tabrizi, S.J.; Banner, S., et al. Proteome-based plasma biomarkers for Alzheimer’s disease. Brain 2006, 129, 3042-3050.
90. Mapstone, M.; Cheema, A.K.; Fiandaca, M.S. Plasma phospholipids identify antecedent memory impairment in older adults. Nat. Med. 2014, 20, 415-418.
91. Kumar, P.; Dezso, Z.; MacKenzie, C.; Oestreicher, J.; Agoulnik, S.; Byrne, M.; Bernier, F.; Yanagimachi, M.; Aoshima, K.; Oda, Y. Circulating mirna biomarkers for Alzheimer’s disease. PLoS ONE 2013, 8, e69807.
92. Kapogiannis, D.; Boxer, A.; Schwartz, J.B.; Abner, E.L.; Biragyn, A.; Masharani, U.; Frassetto, L.; Petersen, R.C.; Miller, B.L.; Goetzl, E.J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J. 2014, 29, 589-596.
93. Goetzl, E.J.; Boxer, A.; Schwartz, J.B.; Abner, E.L.; Petersen, R.C.; Miller, B.L.; Kapogiannis, D. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 2015, 85, 40-47.
94. Allory, Y.; Audard, V.; Fontanges, P.; Ronco, P.; Debiec, H. The l1 cell adhesion molecule is a potential biomarker of human distal nephron injury in acute tubular necrosis. Kidney Int. 2008, 73, 751-758.
95. Rayhan, N.; Sano, T.; Qian, Z.R.; Obari, A.K.; Hirokawa, M. Histological and immunohistochemical study of composite neuroendocrine-exocrine carcinomas of the stomach. J. Med. Investig. 2005, 52, 191-202.
96. Cogswell, J.P.; Ward, J.; Taylor, I.A.; Waters, M.; Shi, Y.; Cannon, B.; Kelnar, K.; Kemppainen, J.; Brown, D.; Chen, C., et al. Identification of mirna changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J. Alzheimer’s Dis. 2008, 14, 27-41.
97. Wang, W.X.; Huang, Q.; Hu, Y.; Stromberg, A.J.; Nelson, P.T. Patterns of microrna expression in normal and early Alzheimer’s disease human temporal cortex: White matter versus gray matter. Acta Neuropathol. 2011, 121, 193-205.
98. Leidinger, P.; Backes, C.; Deutscher, S.; Schmitt, K.; Mueller, S.C.; Frese, K.; Haas, J.; Ruprecht, K.; Paul, F.; Stahler, C., et al. A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol. 2013, 14, doi:10.1186/gb-2013-14-7-r78.
99. Tan, L.; Yu, J.T.; Tan, M.S.; Liu, Q.Y.; Wang, H.F.; Zhang, W.; Jiang, T.; Tan, L. Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer’s disease. J. Alzheimer’s Dis. 2014, 40, 1017-1027.
100. Bekris, L.M.; Lutz, F.; Montine, T.J.; Yu, C.E.; Tsuang, D.; Peskind, E.R.; Leverenz, J.B. MicroRNA in Alzheimer’s disease: An exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers 2013, 18, 455-466.
101. Galimberti, D.; Villa, C.; Fenoglio, C.; Serpente, M.; Ghezzi, L.; Cioffi, S.M.; Arighi, A.; Fumagalli, G.; Scarpini, E. Circulating mirnas as potential biomarkers in Alzheimer’s disease. J. Alzheimer’s Dis. 2014, 42, 1261-1267.
102. Gallo, A.; Tandon, M.; Alevizos, I.; Illei, G.G. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 2012, 7, e30679.
103. Cheng, L.; Doecke, J.D.; Sharples, R.A.; Villemagne, V.L.; Fowler, C.J.; Rembach, A.; Martins, R.N.; Rowe, C.C.; Macaulay, S.L.; Masters, C.L., et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol. Psychiatry 2014, 20, 1188-1196.
104. Margis, R.; Margis, R.; Rieder, C.R. Identification of blood micrornas associated to Parkinsonis disease. J. Biotechnol. 2011, 152, 96-101.
105. Martins, M.; Rosa, A.; Guedes, L.C.; Fonseca, B.V.; Gotovac, K.; Violante, S.; Mestre, T.; Coelho, M.; Rosa, M.M.; Martin, E.R., et al. Convergence of mirna expression profiling, α-synuclein interacton and GWAS in Parkinson’s disease. PLoS ONE 2011, 6, e25443.
106. Cardo, L.F.; Coto, E.; de Mena, L.; Ribacoba, R.; Moris, G.; Menendez, M.; Alvarez, V. Profile of microRNAs in the plasma of Parkinson’s disease patients and healthy controls. J. Neurol. 2013, 260, 1420-1422.
107. Soreq, L.; Bergman, H.; Israel, Z.; Soreq, H. Overlapping molecular signatures in Parkinson’s patients’ leukocytes before and after treatment and in mouse model brain regions. CNS Neurol. Disord. Drug Targets 2013, 12, 1086-1093.
108. Minones-Moyano, E.; Porta, S.; Escaramis, G.; Rabionet, R.; Iraola, S.; Kagerbauer, B.; Espinosa-Parrilla, Y.; Ferrer, I.; Estivill, X.; Marti, E. MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum. Mol. Genet. 2011, 20, 3067-3078.
109. Vella, L.J.; Sharples, R.A.; Lawson, V.A.; Masters, C.L.; Cappai, R.; Hill, A.F. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 2007, 211, 582-590.
110. Fevrier, B.; Vilette, D.; Archer, F.; Loew, D.; Faigle, W.; Vidal, M.; Laude, H.; Raposo, G. Cells release prions in association with exosomes. Proc. Natl. Acad. Sci. USA 2004, 101, 9683-9688.
111. Eisele, Y.S.; Obermuller, U.; Heilbronner, G.; Baumann, F.; Kaeser, S.A.; Wolburg, H.; Walker, L.C.; Staufenbiel, M.; Heikenwalder, M.; Jucker, M. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 2010, 330, 980-982.
112. Hamaguchi, T.; Eisele, Y.S.; Varvel, N.H.; Lamb, B.T.; Walker, L.C.; Jucker, M. The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol. 2012, 123, 31-37.
113. Nath, S.; Agholme, L.; Kurudenkandy, F.R.; Granseth, B.; Marcusson, J.; Hallbeck, M. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J. Neurosci. 2012, 32, 8767-8777.
114. Domert, J.; Rao, S.B.; Agholme, L.; Brorsson, A.C.; Marcusson, J.; Hallbeck, M.; Nath, S. Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol. Dis. 2014, 65, 82-92.
115. Joshi, P.; Turola, E.; Ruiz, A.; Bergami, A.; Libera, D.D.; Benussi, L.; Giussani, P.; Magnani, G.; Comi, G.; Legname, G., et al. Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles. Cell Death Differ. 2014, 21, 582-593.
116. Martins, I.C.; Kuperstein, I.; Wilkinson, H.; Maes, E.; Vanbrabant, M.; Jonckheere, W.; van Gelder, P.; Hartmann, D.; D’Hooge, R.; de Strooper B.; et al. Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice. EMBO J. 2008, 27, 224-233.
117. Guo, J.L.; Lee, V.M. Seeding of normal tau by pathological tau conformers drives pathogenesis of alzheimer-like tangles. J. Biol. Chem. 2011, 286, 15317-15331.
118. Clavaguera, F.; Bolmont, T.; Crowther, R.A.; Abramowski, D.; Frank, S.; Probst, A.; Fraser, G.; Stalder, A.K.; Beibel, M.; Staufenbiel, M., et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell. Biol. 2009, 11, 909-913.
119. Liu, L.; Drouet, V.; Wu, J.W.; Witter, M.P.; Small, S.A.; Clelland, C.; Duff, K. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 2012, 7, e31302.
120. Luk, K.C.; Song, C.; O’Brien, P.; Stieber, A.; Branch, J.R.; Brunden, K.R.; Trojanowski, J.Q.; Lee, V.M. Exogenous α-synuclein fibrils seed the formation of lewy body-like intracellular inclusions in cultured cells. Proc. Natl. Acad. Sci. USA 2009, 106, 20051-20056.
121. Luk, K.C.; Kehm, V.; Carroll, J.; Zhang, B.; O’Brien, P.; Trojanowski, J.Q.; Lee, V.M. Pathological α-synuclein transmission initiates parkinson-like neurodegeneration in nontransgenic mice. Science 2012, 338, 949-953.
122. McLean, P.J.; Kawamata, H.; Ribich, S.; Hyman, B.T. Membrane association and protein conformation of α-synuclein in intact neurons. Effect of Parkinson’s disease-linked mutations. J. Biol. Chem. 2000, 275, 8812-8816.
123. Davidson, W.S.; Jonas, A.; Clayton, D.F.; George, J.M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 1998, 273, 9443-9449.
124. Fire, A.; Xu, S.; Montgomery, M.K.; Kostas, S.A.; Driver, S.E.; Mello, C.C. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans. Nature 1998, 391, 806-811.
125. Tavernarakis, N.; Wang, S.L.; Dorovkov, M.; Ryazanov, A.; Driscoll, M. Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes. Nat. Genet. 2000, 24, 180-183.
126. Cooper, J.M.; Wiklander, P.B.; Nordin, J.Z.; Al-Shawi, R.; Wood, M.J.; Vithlani, M.; Schapira, A.H.; Simons, J.P.; El-Andaloussi, S.; Alvarez-Erviti, L. Systemic exosomal siRNA delivery reduced α-synuclein aggregates in brains of transgenic mice. Mov. Disord. 2014, 29, 1476-1485.
127. Haney, M.J.; Klyachko, N.L.; Zhao, Y.; Gupta, R.; Plotnikova, E.G.; He, Z.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A.V., et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release 2015, 207, 18-30.
128. Ciardiello, C.; Cavallini, L.; Spinelli, C.; Yang, J.; Reis-Sobreiro, M.; de Candia, P.; Minciacchi, V.R.; di Vizio D. Focus on extracellular vesicles: New frontiers of cell-to-cell communication in cancer. Int. J. Mol. Sci. 2016, 17, doi:10.3390/ijms17020175.
129. Iraci, N.; Leonardi, T.; Gessler, F.; Vega, B.; Pluchino, S. Focus on extracellular vesicles: Physiological role and signaling properties of extracellular membrane vesicles. Int. J. Mol. Sci. 2016, 17, doi:10.3390/ijms17020171.
130. Ohno, S.I.; Drummen, G.P.C.; Kuroda, M. Focus on extracellular vesicles: Development of exosome-based therapeutic systems. Int. J. Mol. Sci. 2016, 17, doi:10.3390/ijms17020172.
131. Zhang, B.; Tan, K.H.; Lim, S.K. Focus on extracellular vesicles: Therapeutic efficacy of stem cell-derived extracellular vesicles. Int. J. Mol. Sci. 2016, 17, doi:10.3390/ijms17020174.