Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease?

Neuron

Volumn 91, Issue 5, 2016, Pages 957-973

  Louveau, Antoine ^a   Da Mesquita, Sandro ^a   Kipnis, Jonathan ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; ANTIGEN;

ALZHEIMER DISEASE; AMYLOIDOSIS; BLOOD BRAIN BARRIER; BRAIN BLOOD VESSEL; CENTRAL NERVOUS SYSTEM; CEREBROSPINAL FLUID; CERVICAL LYMPH NODE; CHOROID PLEXUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GENETIC RISK; HUMAN; IMMUNE RESPONSE; IMMUNITY; IMMUNOSURVEILLANCE; INTERSTITIAL FLUID; LYMPH VESSEL; LYMPHATIC SYSTEM; MENINX; MULTIPLE SCLEROSIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN METABOLISM; REVIEW; T LYMPHOCYTE ACTIVATION; ANIMAL; BIOLOGICAL MODEL; IMMUNOLOGY; NERVE CELL; PATHOLOGY; PATHOPHYSIOLOGY; VASCULARIZATION;

ALZHEIMER DISEASE; ANIMALS; CENTRAL NERVOUS SYSTEM; HUMANS; LYMPHATIC SYSTEM; MODELS, IMMUNOLOGICAL; MODELS, NEUROLOGICAL; MULTIPLE SCLEROSIS; NEURONS;

EID: 84995487522     PISSN: 08966273     EISSN: 10974199     Source Type: Journal    
DOI: 10.1016/j.neuron.2016.08.027     Document Type: Review

References (254)

1. Abramov, A.Y., Canevari, L., Duchen, M.R., Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J. Neurosci. 24 (2004), 565–575.
2. Aebischer, D., Iolyeva, M., Halin, C., The inflammatory response of lymphatic endothelium. Angiogenesis 17 (2014), 383–393.
3. Akanuma, S., Ohtsuki, S., Doi, Y., Tachikawa, M., Ito, S., Hori, S., Asashima, T., Hashimoto, T., Yamada, K., Ueda, K., et al. ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier. Neurochem. Int. 52 (2008), 956–961.
4. Alitalo, K., The lymphatic vasculature in disease. Nat. Med. 17 (2011), 1371–1380.
5. Andres, K.H., von Düring, M., Muszynski, K., Schmidt, R.F., Nerve fibres and their terminals of the dura mater encephali of the rat. Anat. Embryol. (Berl.) 175 (1987), 289–301.
6. Andrieu, S., Coley, N., Lovestone, S., Aisen, P.S., Vellas, B., Prevention of sporadic Alzheimer's disease: lessons learned from clinical trials and future directions. Lancet Neurol. 14 (2015), 926–944.
7. Antequera, D., Vargas, T., Ugalde, C., Spuch, C., Molina, J.A., Ferrer, I., Bermejo-Pareja, F., Carro, E., Cytoplasmic gelsolin increases mitochondrial activity and reduces Abeta burden in a mouse model of Alzheimer's disease. Neurobiol. Dis. 36 (2009), 42–50.
8. Arima, Y., Harada, M., Kamimura, D., Park, J.-H., Kawano, F., Yull, F.E., Kawamoto, T., Iwakura, Y., Betz, U.A.K., Márquez, G., et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148 (2012), 447–457.
9. Armulik, A., Genové, G., Mäe, M., Nisancioglu, M.H., Wallgard, E., Niaudet, C., He, L., Norlin, J., Lindblom, P., Strittmatter, K., et al. Pericytes regulate the blood-brain barrier. Nature 468 (2010), 557–561.
10. Aspelund, A., Antila, S., Proulx, S.T., Karlsen, T.V., Karaman, S., Detmar, M., Wiig, H., Alitalo, K., A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212 (2015), 991–999.
11. Bakker, E.N.T.P., Bacskai, B.J., Arbel-Ornath, M., Aldea, R., Bedussi, B., Morris, A.W.J., Weller, R.O., Carare, R.O., Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell. Mol. Neurobiol. 36 (2016), 181–194.
12. Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., Jones, E., Alzheimer's disease. Lancet 377 (2011), 1019–1031.
13. Baluk, P., Fuxe, J., Hashizume, H., Romano, T., Lashnits, E., Butz, S., Vestweber, D., Corada, M., Molendini, C., Dejana, E., McDonald, D.M., Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204 (2007), 2349–2362.
14. Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6 (2000), 916–919.
15. Bartholomäus, I., Kawakami, N., Odoardi, F., Schläger, C., Miljkovic, D., Ellwart, J.W., Klinkert, W.E.F., Flügel-Koch, C., Issekutz, T.B., Wekerle, H., Flügel, A., Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462 (2009), 94–98.
16. Baruch, K., Schwartz, M., CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34 (2013), 11–16.
17. Baruch, K., Ron-Harel, N., Gal, H., Deczkowska, A., Shifrut, E., Ndifon, W., Mirlas-Neisberg, N., Cardon, M., Vaknin, I., Cahalon, L., et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc. Natl. Acad. Sci. USA 110 (2013), 2264–2269.
18. Baruch, K., Deczkowska, A., David, E., Castellano, J.M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346 (2014), 89–93.
19. Baruch, K., Rosenzweig, N., Kertser, A., Deczkowska, A., Sharif, A.M., Spinrad, A., Tsitsou-Kampeli, A., Sarel, A., Cahalon, L., Schwartz, M., Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat. Commun., 6, 2015, 7967.
20. Baruch, K., Deczkowska, A., Rosenzweig, N., Tsitsou-Kampeli, A., Sharif, A.M., Matcovitch-Natan, O., Kertser, A., David, E., Amit, I., Schwartz, M., PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat. Med. 22 (2016), 135–137.
21. Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., et al., Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367 (2012), 795–804.
22. Bazigou, E., Xie, S., Chen, C., Weston, A., Miura, N., Sorokin, L., Adams, R., Muro, A.F., Sheppard, D., Makinen, T., Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev. Cell 17 (2009), 175–186.
23. Bazigou, E., Lyons, O.T.A., Smith, A., Venn, G.E., Cope, C., Brown, N.A., Makinen, T., Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J. Clin. Invest. 121 (2011), 2984–2992.
24. Begley, D.J., Brightman, M.W., Structural and functional aspects of the blood-brain barrier. Prog. Drug Res. 61 (2003), 39–78.
25. Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485 (2012), 512–516.
26. Bénézech, C., Luu, N.-T., Walker, J.A., Kruglov, A.A., Loo, Y., Nakamura, K., Zhang, Y., Nayar, S., Jones, L.H., Flores-Langarica, A., et al. Inflammation-induced formation of fat-associated lymphoid clusters. Nat. Immunol. 16 (2015), 819–828.
27. Benilova, I., Karran, E., De Strooper, B., The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci. 15 (2012), 349–357.
28. Bertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M.F., Schjeide, B.M.M., Hooli, B., Divito, J., Ionita, I., et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83 (2008), 623–632.
29. Betterman, K.L., Harvey, N.L., The lymphatic vasculature: development and role in shaping immunity. Immunol. Rev. 271 (2016), 276–292.
30. Blacker, D., Haines, J.L., Rodes, L., Terwedow, H., Go, R.C., Harrell, L.E., Perry, R.T., Bassett, S.S., Chase, G., Meyers, D., et al. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology 48 (1997), 139–147.
31. Blennow, K., de Leon, M.J., Zetterberg, H., Alzheimer's disease. Lancet 368 (2006), 387–403.
32. Boulton, M., Young, A., Hay, J., Armstrong, D., Flessner, M., Schwartz, M., Johnston, M., Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol. Appl. Neurobiol. 22 (1996), 325–333.
33. Breslin, J.W., Mechanical forces and lymphatic transport. Microvasc. Res. 96 (2014), 46–54.
34. Brightman, M.W., Reese, T.S., Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40 (1969), 648–677.
35. Brkic, M., Balusu, S., Van Wonterghem, E., Gorlé, N., Benilova, I., Kremer, A., Van Hove, I., Moons, L., De Strooper, B., Kanazir, S., et al. Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases. J. Neurosci. 35 (2015), 12766–12778.
36. Brouillard, P., Boon, L., Vikkula, M., Genetics of lymphatic anomalies. J. Clin. Invest. 124 (2014), 898–904.
37. Buckley, C.D., Barone, F., Nayar, S., Bénézech, C., Caamaño, J., Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33 (2015), 715–745.
38. Carare, R.O., Bernardes-Silva, M., Newman, T.A., Page, A.M., Nicoll, J.A., Perry, V.H., Weller, R.O., Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol. Appl. Neurobiol. 34 (2008), 131–144.
39. Card, C.M., Yu, S.S., Swartz, M.A., Emerging roles of lymphatic endothelium in regulating adaptive immunity. J. Clin. Invest. 124 (2014), 943–952.
40. Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., Torres-Aleman, I., Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat. Med. 8 (2002), 1390–1397.
41. Carro, E., Spuch, C., Trejo, J.L., Antequera, D., Torres-Aleman, I., Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J. Neurosci. 25 (2005), 10884–10893.
42. Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J.A., Funk, C.C., Moore, B., DiNunno, N., Rosario, A.M., Cruz, P.E., Verbeeck, C., et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85 (2015), 519–533.
43. Christiansen, A.J., Dieterich, L.C., Ohs, I., Bachmann, S.B., Bianchi, R., Proulx, S.T., Hollmén, M., Aebischer, D., Detmar, M., Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. Oncotarget, 2016, 10.18632/oncotarget.9820 Published online June 5, 2016.
44. Cohen, J.N., Guidi, C.J., Tewalt, E.F., Qiao, H., Rouhani, S.J., Ruddell, A., Farr, A.G., Tung, K.S., Engelhard, V.H., Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 207 (2010), 681–688.
45. Compston, A., Coles, A., Multiple sclerosis. Lancet 359 (2002), 1221–1231.
46. Compston, A., Coles, A., Multiple sclerosis. Lancet 372 (2008), 1502–1517.
47. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 (1993), 921–923.
48. Crossgrove, J.S., Li, G.J., Zheng, W., The choroid plexus removes beta-amyloid from brain cerebrospinal fluid. Exp. Biol. Med. (Maywood) 230 (2005), 771–776.
49. Croxford, A.L., Kurschus, F.C., Waisman, A., Mouse models for multiple sclerosis: historical facts and future implications. Biochim. Biophys. Acta 1812 (2011), 177–183.
50. Czeloth, N., Bernhardt, G., Hofmann, F., Genth, H., Förster, R., Sphingosine-1-phosphate mediates migration of mature dendritic cells. J. Immunol. 175 (2005), 2960–2967.
51. D'Alessio, S., Correale, C., Tacconi, C., Gandelli, A., Pietrogrande, G., Vetrano, S., Genua, M., Arena, V., Spinelli, A., Peyrin-Biroulet, L., et al. VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J. Clin. Invest. 124 (2014), 3863–3878.
52. Danussi, C., Spessotto, P., Petrucco, A., Wassermann, B., Sabatelli, P., Montesi, M., Doliana, R., Bressan, G.M., Colombatti, A., Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. Mol. Cell. Biol. 28 (2008), 4026–4039.
53. de Vos, A.F., van Meurs, M., Brok, H.P., Boven, L.A., Hintzen, R.Q., van der Valk, P., Ravid, R., Rensing, S., Boon, L., ’t Hart, B.A., Laman, J.D., Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J. Immunol. 169 (2002), 5415–5423.
54. Deane, R., Du Yan, S., Submamaryan, R.K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 9 (2003), 907–913.
55. Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H.W., et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43 (2004), 333–344.
56. Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M.B., Holtzman, D.M., Zlokovic, B.V., apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J. Clin. Invest. 118 (2008), 4002–4013.
57. Debes, G.F., Arnold, C.N., Young, A.J., Krautwald, S., Lipp, M., Hay, J.B., Butcher, E.C., Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6 (2005), 889–894.
58. Douglass, J., Graves, P., Gordon, S., Self-care for management of secondary lymphedema: a systematic review. PLoS Negl. Trop. Dis., 10, 2016, e0004740.
59. Elewa, Y.H.A., Ichii, O., Otsuka, S., Hashimoto, Y., Kon, Y., Characterization of mouse mediastinal fat-associated lymphoid clusters. Cell Tissue Res. 357 (2014), 731–741.
60. Engelhardt, B., Wolburg-Buchholz, K., Wolburg, H., Involvement of the choroid plexus in central nervous system inflammation. Microsc. Res. Tech. 52 (2001), 112–129.
61. Erickson, M.A., Banks, W.A., Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J. Cereb. Blood Flow Metab. 33 (2013), 1500–1513.
62. Erickson, M.A., Hansen, K., Banks, W.A., Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: protection by the antioxidant N-acetylcysteine. Brain Behav. Immun. 26 (2012), 1085–1094.
63. Fagan, A.M., Xiong, C., Jasielec, M.S., Bateman, R.J., Goate, A.M., Benzinger, T.L.S., Ghetti, B., Martins, R.N., Masters, C.L., Mayeux, R., et al., Dominantly Inherited Alzheimer Network. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci. Transl. Med., 6, 2014, 226ra30.
64. Farez, M.F., Mascanfroni, I.D., Méndez-Huergo, S.P., Yeste, A., Murugaiyan, G., Garo, L.P., Balbuena Aguirre, M.E., Patel, B., Ysrraelit, M.C., Zhu, C., et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162 (2015), 1338–1352.
65. Fernandez, O., Rodriguez-Antiguedad, A., Olascoaga, J., Oreja-Guevara, C., Prieto, J.M., Mendibe-Bilbao, M.M., Garcia-Merino, J.A., Ramio-Torrenta, L., Ginestal, R., Meca-Lallana, J.E., et al. Review of the novelties from the 31st ECTRIMS Congress, 2015, presented at the 8th Post-ECTRIMS meeting. Rev. Neurol. 62 (2016), 559–569.
66. Fitz, N.F., Cronican, A.A., Saleem, M., Fauq, A.H., Chapman, R., Lefterov, I., Koldamova, R., Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J. Neurosci. 32 (2012), 13125–13136.
67. Flügel, A., Berkowicz, T., Ritter, T., Labeur, M., Jenne, D.E., Li, Z., Ellwart, J.W., Willem, M., Lassmann, H., Wekerle, H., Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14 (2001), 547–560.
68. Foldi, M., Csanda, E., Obal, F., Madarasz, I., Szeghy, G., Zoltan, O., Uber Wirkungen der Unterbindung der Lymphgefasse und Lymphknoten des Halses auf das Zentralnervensystem im Tierversuch. Gesamte Exp. Med 137 (1963), 483–510.
69. Furman, J.L., Sama, D.M., Gant, J.C., Beckett, T.L., Murphy, M.P., Bachstetter, A.D., Van Eldik, L.J., Norris, C.M., Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease. J. Neurosci. 32 (2012), 16129–16140.
70. Furtado, G.C., Marcondes, M.C.G., Latkowski, J.-A., Tsai, J., Wensky, A., Lafaille, J.J., Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J. Immunol. 181 (2008), 4648–4655.
71. Goldmann, J., Kwidzinski, E., Brandt, C., Mahlo, J., Richter, D., Bechmann, I., T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J. Leukoc. Biol. 80 (2006), 797–801.
72. Gollmann, G., Neuwirt, H., Tripp, C.H., Mueller, H., Konwalinka, G., Heufler, C., Romani, N., Tiefenthaler, M., Sphingosine-1-phosphate receptor type-1 agonism impairs blood dendritic cell chemotaxis and skin dendritic cell migration to lymph nodes under inflammatory conditions. Int. Immunol. 20 (2008), 911–923.
73. Goodin, D.S., The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handb. Clin. Neurol. 122 (2014), 231–266.
74. Greenberg, S.M., Gurol, M.E., Rosand, J., Smith, E.E., Amyloid angiopathy-related vascular cognitive impairment. Stroke 35:Suppl 1 (2004), 2616–2619.
75. Greter, M., Hofmann, J., Becher, B., Neo-lymphoid aggregates in the adult liver can initiate potent cell-mediated immunity. PLoS Biol., 7, 2009, e1000109.
76. Griciuc, A., Serrano-Pozo, A., Parrado, A.R., Lesinski, A.N., Asselin, C.N., Mullin, K., Hooli, B., Choi, S.H., Hyman, B.T., Tanzi, R.E., Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78 (2013), 631–643.
77. Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J.S.K., Younkin, S., et al., Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368 (2013), 117–127.
78. Guillot-Sestier, M.-V., Doty, K.R., Gate, D., Rodriguez, J. Jr., Leung, B.P., Rezai-Zadeh, K., Town, T., Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85 (2015), 534–548.
79. Hardy, J., Selkoe, D.J., The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 (2002), 353–356.
80. Harling-Berg, C.J., Knopf, P.M., Cserr, H.F., Myelin basic protein infused into cerebrospinal fluid suppresses experimental autoimmune encephalomyelitis. J. Neuroimmunol. 35 (1991), 45–51.
81. Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M.L., Pahwa, J.S., Moskvina, V., Dowzell, K., Williams, A., et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41 (2009), 1088–1093.
82. Harris, M.G., Hulseberg, P., Ling, C., Karman, J., Clarkson, B.D., Harding, J.S., Zhang, M., Sandor, A., Christensen, K., Nagy, A., et al. Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci. Rep., 4, 2014, 4422.
83. Hartz, A.M.S., Zhong, Y., Wolf, A., LeVine, H. 3rd, Miller, D.S., Bauer, B., Aβ40 reduces P-glycoprotein at the blood-brain barrier through the ubiquitin-proteasome pathway. J. Neurosci. 36 (2016), 1930–1941.
84. Hasegawa-Ishii, S., Shimada, A., Inaba, M., Li, M., Shi, M., Kawamura, N., Takei, S., Chiba, Y., Hosokawa, M., Ikehara, S., Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus. Brain Behav. Immun. 29 (2013), 82–97.
85. Hawkes, C.A., Härtig, W., Kacza, J., Schliebs, R., Weller, R.O., Nicoll, J.A., Carare, R.O., Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121 (2011), 431–443.
86. Hawkes, C.A., Gatherer, M., Sharp, M.M., Dorr, A., Yuen, H.M., Kalaria, R., Weller, R.O., Carare, R.O., Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell 12 (2013), 224–236.
87. Hawkes, C.A., Jayakody, N., Johnston, D.A., Bechmann, I., Carare, R.O., Failure of perivascular drainage of β-amyloid in cerebral amyloid angiopathy. Brain Pathol. 24 (2014), 396–403.
88. He, J., Hsuchou, H., He, Y., Kastin, A.J., Wang, Y., Pan, W., Sleep restriction impairs blood-brain barrier function. J. Neurosci. 34 (2014), 14697–14706.
89. Hong, S., Quintero-Monzon, O., Ostaszewski, B.L., Podlisny, D.R., Cavanaugh, W.T., Yang, T., Holtzman, D.M., Cirrito, J.R., Selkoe, D.J., Dynamic analysis of amyloid β-protein in behaving mice reveals opposing changes in ISF versus parenchymal Aβ during age-related plaque formation. J. Neurosci. 31 (2011), 15861–15869.
90. Hong, S., Beja-Glasser, V.F., Nfonoyim, B.M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K.M., Shi, Q., Rosenthal, A., Barres, B.A., et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352 (2016), 712–716.
91. Howell, O.W., Reeves, C.A., Nicholas, R., Carassiti, D., Radotra, B., Gentleman, S.M., Serafini, B., Aloisi, F., Roncaroli, F., Magliozzi, R., Reynolds, R., Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134 (2011), 2755–2771.
92. Iliff, J.J., Wang, M., Liao, Y., Plogg, B.A., Peng, W., Gundersen, G.A., Benveniste, H., Vates, G.E., Deane, R., Goldman, S.A., et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med., 4, 2012, 147ra111.
93. Iliff, J.J., Chen, M.J., Plog, B.A., Zeppenfeld, D.M., Soltero, M., Yang, L., Singh, I., Deane, R., Nedergaard, M., Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34 (2014), 16180–16193.
94. Ittner, L.M., Götz, J., Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease. Nat. Rev. Neurosci. 12 (2011), 65–72.
95. Ivanov, S., Scallan, J.P., Kim, K.-W., Werth, K., Johnson, M.W., Saunders, B.T., Wang, P.L., Kuan, E.L., Straub, A.C., Ouhachi, M., et al. CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J. Clin. Invest. 126 (2016), 1581–1591.
96. Jay, T.R., Miller, C.M., Cheng, P.J., Graham, L.C., Bemiller, S., Broihier, M.L., Xu, G., Margevicius, D., Karlo, J.C., Sousa, G.L., et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212 (2015), 287–295.
97. Jeltema, H.-R., Kuijlen, J.M.A., Hoving, E.W., Acute hydrocephalus in a child with a third ventricle arachnoid cyst and coincidental enteroviral meningitis. Childs Nerv. Syst. 30 (2014), 1129–1133.
98. Jessen, N.A., Munk, A.S.F., Lundgaard, I., Nedergaard, M., The glymphatic system: a beginner's guide. Neurochem. Res. 40 (2015), 2583–2599.
99. Jiang, Q., Jin, S., Jiang, Y., Liao, M., Feng, R., Zhang, L., Liu, G., Hao, J., Alzheimer's disease variants with the genome-wide significance are significantly enriched in immune pathways and active in immune cells. Mol. Neurobiol., 2016, 10.1007/s12035-015-9670-8 Published online January 9, 2016.
100. Johanson, C., McMillan, P., Tavares, R., Spangenberger, A., Duncan, J., Silverberg, G., Stopa, E., Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease. Cerebrospinal Fluid Res., 1, 2004, 3.
101. Johnson, L.A., Jackson, D.G., Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int. Immunol. 22 (2010), 839–849.
102. Johnson, L.A., Jackson, D.G., The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics. J. Cell Sci. 126 (2013), 5259–5270.
103. Johnson, L.A., Clasper, S., Holt, A.P., Lalor, P.F., Baban, D., Jackson, D.G., An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J. Exp. Med. 203 (2006), 2763–2777.
104. Johnston, M., Zakharov, A., Papaiconomou, C., Salmasi, G., Armstrong, D., Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res., 1, 2004, 2.
105. Kabashima, K., Shiraishi, N., Sugita, K., Mori, T., Onoue, A., Kobayashi, M., Sakabe, J., Yoshiki, R., Tamamura, H., Fujii, N., et al. CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am. J. Pathol. 171 (2007), 1249–1257.
106. Kaji, C., Tomooka, M., Kato, Y., Kojima, H., Sawa, Y., The expression of podoplanin and classic cadherins in the mouse brain. J. Anat. 220 (2012), 435–446.
107. Kajiya, K., Sawane, M., Huggenberger, R., Detmar, M., Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J. Invest. Dermatol. 129 (2009), 1292–1298.
108. Kalof, A.N., Cooper, K., D2-40 immunohistochemistry—so far!. Adv. Anat. Pathol. 16 (2009), 62–64.
109. Kaminski, M., Bechmann, I., Pohland, M., Kiwit, J., Nitsch, R., Glumm, J., Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J. Leukoc. Biol. 92 (2012), 31–39.
110. Kanady, J.D., Dellinger, M.T., Munger, S.J., Witte, M.H., Simon, A.M., Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev. Biol. 354 (2011), 253–266.
111. Karikoski, M., Irjala, H., Maksimow, M., Miiluniemi, M., Granfors, K., Hernesniemi, S., Elima, K., Moldenhauer, G., Schledzewski, K., Kzhyshkowska, J., et al. Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur. J. Immunol. 39 (2009), 3477–3487.
112. Katsuta, H., Fukushima, Y., Maruyama, K., Hirashima, M., Nishida, K., Nishikawa, S., Uemura, A., EphrinB2-EphB4 signals regulate formation and maintenance of funnel-shaped valves in corneal lymphatic capillaries. Invest. Ophthalmol. Vis. Sci. 54 (2013), 4102–4108.
113. Kazenwadel, J., Harvey, N.L., Morphogenesis of the lymphatic vasculature: a focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels. Dev. Dyn. 245 (2016), 209–219.
114. Kazenwadel, J., Betterman, K.L., Chong, C.-E., Stokes, P.H., Lee, Y.K., Secker, G.A., Agalarov, Y., Demir, C.S., Lawrence, D.M., Sutton, D.L., et al. GATA2 is required for lymphatic vessel valve development and maintenance. J. Clin. Invest. 125 (2015), 2979–2994.
115. Kerjaschki, D., The lymphatic vasculature revisited. J. Clin. Invest. 124 (2014), 874–877.
116. Kida, S., Pantazis, A., Weller, R.O., CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19 (1993), 480–488.
117. Kim, H., Kataru, R.P., Koh, G.Y., Inflammation-associated lymphangiogenesis: a double-edged sword?. J. Clin. Invest. 124 (2014), 936–942.
118. Kimbrough, I.F., Robel, S., Roberson, E.D., Sontheimer, H., Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138 (2015), 3716–3733.
119. Kipnis, J., Gadani, S., Derecki, N.C., Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12 (2012), 663–669.
120. Koltowska, K., Betterman, K.L., Harvey, N.L., Hogan, B.M., Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature. Development 140 (2013), 1857–1870.
121. Kress, B.T., Iliff, J.J., Xia, M., Wang, M., Wei, H.S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J.A., et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76 (2014), 845–861.
122. Kuan, E.L., Ivanov, S., Bridenbaugh, E.A., Victora, G., Wang, W., Childs, E.W., Platt, A.M., Jakubzick, C.V., Mason, R.J., Gashev, A.A., et al. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J. Immunol. 194 (2015), 5200–5210.
123. Kuerten, S., Schickel, A., Kerkloh, C., Recks, M.S., Addicks, K., Ruddle, N.H., Lehmann, P.V., Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response. Acta Neuropathol. 124 (2012), 861–873.
124. Kunert, C., Baish, J.W., Liao, S., Padera, T.P., Munn, L.L., Mechanobiological oscillators control lymph flow. Proc. Natl. Acad. Sci. USA 112 (2015), 10938–10943.
125. Kunis, G., Baruch, K., Rosenzweig, N., Kertser, A., Miller, O., Berkutzki, T., Schwartz, M., IFN-γ-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain 136 (2013), 3427–3440.
126. Lake, J., Weller, R.O., Phillips, M.J., Needham, M., Lymphocyte targeting of the brain in adoptive transfer cryolesion-EAE. J. Pathol. 187 (1999), 259–265.
127. Lam, F.C., Liu, R., Lu, P., Shapiro, A.B., Renoir, J.M., Sharom, F.J., Reiner, P.B., beta-Amyloid efflux mediated by p-glycoprotein. J. Neurochem. 76 (2001), 1121–1128.
128. Laman, J.D., Weller, R.O., Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J. Neuroimmune Pharmacol. 8 (2013), 840–856.
129. Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M.J., Tavernier, B., et al., European Alzheimer's Disease Initiative Investigators. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41 (2009), 1094–1099.
130. Lambert, J.C., Ibrahim-Verbaas, C.A., Harold, D., Naj, A.C., Sims, R., Bellenguez, C., DeStafano, A.L., Bis, J.C., Beecham, G.W., Grenier-Boley, B., et al. European Alzheimer's Disease Initiative (EADI) Genetic and Environmental Risk in Alzheimer's Disease Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45 (2013), 1452–1458.
131. Leak, L.V., The structure of lymphatic capillaries in lymph formation. Fed. Proc. 35 (1976), 1863–1871.
132. Leak, L.V., Burke, J.F., Ultrastructural studies on the lymphatic anchoring filaments. J. Cell Biol. 36 (1968), 129–149.
133. Li, H., Monien, B.H., Fradinger, E.A., Urbanc, B., Bitan, G., Biophysical characterization of Abeta42 C-terminal fragments: inhibitors of Abeta42 neurotoxicity. Biochemistry 49 (2010), 1259–1267.
134. Liao, A., Nitsch, R.M., Greenberg, S.M., Finckh, U., Blacker, D., Albert, M., Rebeck, G.W., Gomez-Isla, T., Clatworthy, A., Binetti, G., et al. Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease. Hum. Mol. Genet. 7 (1998), 1953–1956.
135. Liblau, R.S., Gonzalez-Dunia, D., Wiendl, H., Zipp, F., Neurons as targets for T cells in the nervous system. Trends Neurosci. 36 (2013), 315–324.
136. Liddelow, S.A., Temple, S., Møllgård, K., Gehwolf, R., Wagner, A., Bauer, H., Bauer, H.-C., Phoenix, T.N., Dziegielewska, K.M., Saunders, N.R., Molecular characterisation of transport mechanisms at the developing mouse blood-CSF interface: a transcriptome approach. PLoS ONE, 7, 2012, e33554.
137. Lim, H.Y., Thiam, C.H., Yeo, K.P., Bisoendial, R., Hii, C.S., McGrath, K.C.Y., Tan, K.W., Heather, A., Alexander, J.S.J., Angeli, V., Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 17 (2013), 671–684.
138. Liu, Q., Zerbinatti, C.V., Zhang, J., Hoe, H.-S., Wang, B., Cole, S.L., Herz, J., Muglia, L., Bu, G., Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56 (2007), 66–78.
139. Locatelli, G., Wörtge, S., Buch, T., Ingold, B., Frommer, F., Sobottka, B., Krüger, M., Karram, K., Bühlmann, C., Bechmann, I., et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat. Neurosci. 15 (2012), 543–550.
140. Louveau, A., Smirnov, I., Keyes, T.J., Eccles, J.D., Rouhani, S.J., Peske, J.D., Derecki, N.C., Castle, D., Mandell, J.W., Lee, K.S., et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523 (2015), 337–341.
141. Louveau, A., Harris, T.H., Kipnis, J., Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36 (2015), 569–577.
142. Lukacs-Kornek, V., Malhotra, D., Fletcher, A.L., Acton, S.E., Elpek, K.G., Tayalia, P., Collier, A.R., Turley, S.J., Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat. Immunol. 12 (2011), 1096–1104.
143. Lund, A.W., Duraes, F.V., Hirosue, S., Raghavan, V.R., Nembrini, C., Thomas, S.N., Issa, A., Hugues, S., Swartz, M.A., VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 1 (2012), 191–199.
144. Mackic, J.B., Stins, M., McComb, J.G., Calero, M., Ghiso, J., Kim, K.S., Yan, S.D., Stern, D., Schmidt, A.M., Frangione, B., Zlokovic, B.V., Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 102 (1998), 734–743.
145. Magliozzi, R., Howell, O., Vora, A., Serafini, B., Nicholas, R., Puopolo, M., Reynolds, R., Aloisi, F., Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130 (2007), 1089–1104.
146. Mäkinen, T., Adams, R.H., Bailey, J., Lu, Q., Ziemiecki, A., Alitalo, K., Klein, R., Wilkinson, G.A., PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 19 (2005), 397–410.
147. Malhotra, D., Fletcher, A.L., Astarita, J., Lukacs-Kornek, V., Tayalia, P., Gonzalez, S.F., Elpek, K.G., Chang, S.K., Knoblich, K., Hemler, M.E., et al., Immunological Genome Project Consortium. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13 (2012), 499–510.
148. Marques, F., Sousa, J.C., Sousa, N., Palha, J.A., Blood-brain-barriers in aging and in Alzheimer's disease. Mol. Neurodegener., 8, 2013, 38.
149. Matarin, M., Salih, D.A., Yasvoina, M., Cummings, D.M., Guelfi, S., Liu, W., Nahaboo Solim, M.A., Moens, T.G., Paublete, R.M., Ali, S.S., et al. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 10 (2015), 633–644.
150. Mawuenyega, K.G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J.C., Yarasheski, K.E., Bateman, R.J., Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science, 330, 2010, 1774.
151. Medeiros, R., LaFerla, F.M., Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp. Neurol. 239 (2013), 133–138.
152. MeinL, E., Hoch, R.M., Dornmair, K., de Waal Malefyt, R., Bontrop, R.E., Jonker, M., Lassmann, H., Hohlfeld, R., Wekerle, H., ’t Hart, B.A., Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques. Am. J. Pathol. 150 (1997), 445–453.
153. Mesquita, S.D., Ferreira, A.C., Gao, F., Coppola, G., Geschwind, D.H., Sousa, J.C., Correia-Neves, M., Sousa, N., Palha, J.A., Marques, F., The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease. Brain Behav. Immun. 49 (2015), 280–292.
154. Michaud, J.-P., Bellavance, M.-A., Préfontaine, P., Rivest, S., Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 5 (2013), 646–653.
155. Miller, S.D., Vanderlugt, C.L., Lenschow, D.J., Pope, J.G., Karandikar, N.J., Dal Canto, M.C., Bluestone, J.A., Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity 3 (1995), 739–745.
156. Miller, S.D., McMahon, E.J., Schreiner, B., Bailey, S.L., Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann. N Y Acad. Sci. 1103 (2007), 179–191.
157. Miteva, D.O., Rutkowski, J.M., Dixon, J.B., Kilarski, W., Shields, J.D., Swartz, M.A., Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106 (2010), 920–931.
158. Mollanji, R., Bozanovic-Sosic, R., Zakharov, A., Makarian, L., Johnston, M.G., Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282 (2002), R1593–R1599.
159. Munn, L.L., Mechanobiology of lymphatic contractions. Semin. Cell Dev. Biol. 38 (2015), 67–74.
160. Nagra, G., Koh, L., Zakharov, A., Armstrong, D., Johnston, M., Quantification of cerebrospinal fluid transport across the cribriform plate into lymphatics in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291 (2006), R1383–R1389.
161. Naj, A.C., Jun, G., Beecham, G.W., Wang, L.-S., Vardarajan, B.N., Buros, J., Gallins, P.J., Buxbaum, J.D., Jarvik, G.P., Crane, P.K., et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43 (2011), 436–441.
162. Newman, B., Lose, F., Kedda, M.-A., Francois, M., Ferguson, K., Janda, M., Yates, P., Spurdle, A.B., Hayes, S.C., Possible genetic predisposition to lymphedema after breast cancer. Lymphat. Res. Biol. 10 (2012), 2–13.
163. Nichols, L.A., Chen, Y., Colella, T.A., Bennett, C.L., Clausen, B.E., Engelhard, V.H., Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J. Immunol. 179 (2007), 993–1003.
164. Nörder, M., Gutierrez, M.G., Zicari, S., Cervi, E., Caruso, A., Guzmán, C.A., Lymph node-derived lymphatic endothelial cells express functional costimulatory molecules and impair dendritic cell-induced allogenic T-cell proliferation. FASEB J. 26 (2012), 2835–2846.
165. O'Donnell, J., Ding, F., Nedergaard, M., Distinct functional states of astrocytes during sleep and wakefulness: is norepinephrine the master regulator?. Curr Sleep Med Rep 1 (2015), 1–8.
166. Odoardi, F., Sie, C., Streyl, K., Ulaganathan, V.K., Schläger, C., Lodygin, D., Heckelsmiller, K., Nietfeld, W., Ellwart, J., Klinkert, W.E.F., et al. T cells become licensed in the lung to enter the central nervous system. Nature 488 (2012), 675–679.
167. Ohl, L., Mohaupt, M., Czeloth, N., Hintzen, G., Kiafard, Z., Zwirner, J., Blankenstein, T., Henning, G., Förster, R., CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21 (2004), 279–288.
168. Orre, M., Kamphuis, W., Osborn, L.M., Jansen, A.H.P., Kooijman, L., Bossers, K., Hol, E.M., Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol. Aging 35 (2014), 2746–2760.
169. Palanichamy, A., Apeltsin, L., Kuo, T.C., Sirota, M., Wang, S., Pitts, S.J., Sundar, P.D., Telman, D., Zhao, L.Z., Derstine, M., et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci. Transl. Med., 6, 2014, 248ra106.
170. Palop, J.J., Chin, J., Roberson, E.D., Wang, J., Thwin, M.T., Bien-Ly, N., Yoo, J., Ho, K.O., Yu, G.-Q., Kreitzer, A., et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55 (2007), 697–711.
171. Pascale, C.L., Miller, M.C., Chiu, C., Boylan, M., Caralopoulos, I.N., Gonzalez, L., Johanson, C.E., Silverberg, G.D., Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent. Fluids Barriers CNS, 8, 2011, 21.
172. Peng, W., Achariyar, T.M., Li, B., Liao, Y., Mestre, H., Hitomi, E., Regan, S., Kasper, T., Peng, S., Ding, F., et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol. Dis. 93 (2016), 215–225.
173. Pepys, M.B., Herbert, J., Hutchinson, W.L., Tennent, G.A., Lachmann, H.J., Gallimore, J.R., Lovat, L.B., Bartfai, T., Alanine, A., Hertel, C., et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417 (2002), 254–259.
174. Peters, A., Pitcher, L.A., Sullivan, J.M., Mitsdoerffer, M., Acton, S.E., Franz, B., Wucherpfennig, K., Turley, S., Carroll, M.C., Sobel, R.A., et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35 (2011), 986–996.
175. Peters, A., Burkett, P.R., Sobel, R.A., Buckley, C.D., Watson, S.P., Bettelli, E., Kuchroo, V.K., Podoplanin negatively regulates CD4+ effector T cell responses. J. Clin. Invest. 125 (2015), 129–140.
176. Petrova, T.V., Karpanen, T., Norrmén, C., Mellor, R., Tamakoshi, T., Finegold, D., Ferrell, R., Kerjaschki, D., Mortimer, P., Ylä-Herttuala, S., et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat. Med. 10 (2004), 974–981.
177. Pette, M., Fujita, K., Kitze, B., Whitaker, J.N., Albert, E., Kappos, L., Wekerle, H., Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 40 (1990), 1770–1776.
178. Phillips, M.J., Needham, M., Weller, R.O., Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat. J. Pathol. 182 (1997), 457–464.
179. Pivetta, E., Wassermann, B., Del Bel Belluz, L., Danussi, C., Modica, T.M.E., Maiorani, O., Bosisio, G., Boccardo, F., Canzonieri, V., Colombatti, A., Spessotto, P., Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model. Clin. Sci. 130 (2016), 1221–1236.
180. Podgrabinska, S., Kamalu, O., Mayer, L., Shimaoka, M., Snoeck, H., Randolph, G.J., Skobe, M., Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J. Immunol. 183 (2009), 1767–1779.
181. Popescu, B.F., Lucchinetti, C.F., Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol., 12, 2012, 11.
182. Potter, R., Patterson, B.W., Elbert, D.L., Ovod, V., Kasten, T., Sigurdson, W., Mawuenyega, K., Blazey, T., Goate, A., Chott, R., et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci. Transl. Med., 5, 2013, 189ra77.
183. Prineas, J.W., Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 203 (1979), 1123–1125.
184. Rangroo Thrane, V., Thrane, A.S., Plog, B.A., Thiyagarajan, M., Iliff, J.J., Deane, R., Nagelhus, E.A., Nedergaard, M., Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci. Rep., 3, 2013, 2582, 10.1038/srep02582.
185. Ransohoff, R.M., Engelhardt, B., The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12 (2012), 623–635.
186. Reboldi, A., Coisne, C., Baumjohann, D., Benvenuto, F., Bottinelli, D., Lira, S., Uccelli, A., Lanzavecchia, A., Engelhardt, B., Sallusto, F., C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10 (2009), 514–523.
187. Rennels, M.L., Gregory, T.F., Blaumanis, O.R., Fujimoto, K., Grady, P.A., Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 326 (1985), 47–63.
188. Rennels, M.L., Blaumanis, O.R., Grady, P.A., Rapid solute transport throughout the brain via paravascular fluid pathways. Adv. Neurol. 52 (1990), 431–439.
189. Rouzaut, A., Garasa, S., Teijeira, A., González, I., Martinez-Forero, I., Suarez, N., Larrea, E., Alfaro, C., Palazón, A., Dubrot, J., et al. Dendritic cells adhere to and transmigrate across lymphatic endothelium in response to IFN-α. Eur. J. Immunol. 40 (2010), 3054–3063.
190. Sabine, A., Agalarov, Y., Maby-El Hajjami, H., Jaquet, M., Hägerling, R., Pollmann, C., Bebber, D., Pfenniger, A., Miura, N., Dormond, O., et al. Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev. Cell 22 (2012), 430–445.
191. Saeki, H., Moore, A.M., Brown, M.J., Hwang, S.T., Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J. Immunol. 162 (1999), 2472–2475.
192. Sagare, A., Deane, R., Bell, R.D., Johnson, B., Hamm, K., Pendu, R., Marky, A., Lenting, P.J., Wu, Z., Zarcone, T., et al. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat. Med. 13 (2007), 1029–1031.
193. Sagare, A.P., Bell, R.D., Zhao, Z., Ma, Q., Winkler, E.A., Ramanathan, A., Zlokovic, B.V., Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun., 4, 2013, 2932.
194. Sawa, Y., Tsuruga, E., The expression of E-selectin and chemokines in the cultured human lymphatic endothelium with lipopolysaccharides. J. Anat. 212 (2008), 654–663.
195. Schläger, C., Körner, H., Krueger, M., Vidoli, S., Haberl, M., Mielke, D., Brylla, E., Issekutz, T., Cabañas, C., Nelson, P.J., et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530 (2016), 349–353.
196. Schley, D., Carare-Nnadi, R., Please, C.P., Perry, V.H., Weller, R.O., Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J. Theor. Biol. 238 (2006), 962–974.
197. Schulte-Merker, S., Sabine, A., Petrova, T.V., Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol. 193 (2011), 607–618.
198. Shayo, M., McLay, R.N., Kastin, A.J., Banks, W.A., The putative blood-brain barrier transporter for the beta-amyloid binding protein apolipoprotein j is saturated at physiological concentrations. Life Sci. 60 (1997), PL115–PL118.
199. Shibata, M., Yamada, S., Kumar, S.R., Calero, M., Bading, J., Frangione, B., Holtzman, D.M., Miller, C.A., Strickland, D.K., Ghiso, J., Zlokovic, B.V., Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest. 106 (2000), 1489–1499.
200. Slavin, A., Ewing, C., Liu, J., Ichikawa, M., Slavin, J., Bernard, C.C., Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity 28 (1998), 109–120.
201. Steinman, L., Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat. Rev. Drug Discov. 4 (2005), 510–518.
202. Steinman, L., Immunology of relapse and remission in multiple sclerosis. Annu. Rev. Immunol. 32 (2014), 257–281.
203. Steinman, L., Zamvil, S.S., Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol. 26 (2005), 565–571.
204. Stern, J.N.H., Yaari, G., Vander Heiden, J.A., Church, G., Donahue, W.F., Hintzen, R.Q., Huttner, A.J., Laman, J.D., Nagra, R.M., Nylander, A., et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci. Transl. Med., 6, 2014, 248ra107.
205. Sugimoto, T., Uranishi, R., Yamada, T., Gradually progressive symptoms of normal pressure hydrocephalus caused by an arachnoid cyst in the fourth ventricle: a case report. World. Neurosurg. 85 (2016), 364.e19–364.e22.
206. Sun, B., Halabisky, B., Zhou, Y., Palop, J.J., Yu, G., Mucke, L., Gan, L., Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer's disease. Cell Stem Cell 5 (2009), 624–633.
207. Suzuki, N., Cheung, T.T., Cai, X.D., Odaka, A., Otvos, L. Jr., Eckman, C., Golde, T.E., Younkin, S.G., An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264 (1994), 1336–1340.
208. Sweet, D.T., Jiménez, J.M., Chang, J., Hess, P.R., Mericko-Ishizuka, P., Fu, J., Xia, L., Davies, P.F., Kahn, M.L., Lymph flow regulates collecting lymphatic vessel maturation in vivo. J. Clin. Invest. 125 (2015), 2995–3007.
209. Takamatsu, H., Takegahara, N., Nakagawa, Y., Tomura, M., Taniguchi, M., Friedel, R.H., Rayburn, H., Tessier-Lavigne, M., Yoshida, Y., Okuno, T., et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat. Immunol. 11 (2010), 594–600.
210. Tammela, T., Alitalo, K., Lymphangiogenesis: molecular mechanisms and future promise. Cell 140 (2010), 460–476.
211. Tanzi, R.E., TREM2 and risk of Alzheimer's disease—friend or foe?. N. Engl. J. Med. 372 (2015), 2564–2565.
212. Tarasoff-Conway, J.M., Carare, R.O., Osorio, R.S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B.V., et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11 (2015), 457–470.
213. Teijeira, A., Rouzaut, A., Melero, I., Initial afferent lymphatic vessels controlling outbound leukocyte traffic from skin to lymph nodes. Front. Immunol., 4, 2013, 433.
214. Tewalt, E.F., Cohen, J.N., Rouhani, S.J., Guidi, C.J., Qiao, H., Fahl, S.P., Conaway, M.R., Bender, T.P., Tung, K.S., Vella, A.T., et al. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 120 (2012), 4772–4782.
215. Thal, D.R., Griffin, W.S.T., de Vos, R.A.I., Ghebremedhin, E., Cerebral amyloid angiopathy and its relationship to Alzheimer's disease. Acta Neuropathol. 115 (2008), 599–609.
216. Thanopoulou, K., Fragkouli, A., Stylianopoulou, F., Georgopoulos, S., Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc. Natl. Acad. Sci. USA 107 (2010), 20816–20821.
217. Tomei, A.A., Siegert, S., Britschgi, M.R., Luther, S.A., Swartz, M.A., Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J. Immunol. 183 (2009), 4273–4283.
218. Torzicky, M., Viznerova, P., Richter, S., Strobl, H., Scheinecker, C., Foedinger, D., Riedl, E., Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) and CD99 are critical in lymphatic transmigration of human dendritic cells. J. Invest. Dermatol. 132 (2012), 1149–1157.
219. Traka, M., Arasi, K., Avila, R.L., Podojil, J.R., Christakos, A., Miller, S.D., Soliven, B., Popko, B., A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain 133 (2010), 3017–3029.
220. Traka, M., Podojil, J.R., McCarthy, D.P., Miller, S.D., Popko, B., Oligodendrocyte death results in immune-mediated CNS demyelination. Nat. Neurosci. 19 (2016), 65–74.
221. Urra, X., Miró, F., Chamorro, A., Planas, A.M., Antigen-specific immune reactions to ischemic stroke. Front. Cell. Neurosci., 8, 2014, 278.
222. van Zwam, M., Huizinga, R., Heijmans, N., van Meurs, M., Wierenga-Wolf, A.F., Melief, M.-J., Hintzen, R.Q., ’t Hart, B.A., Amor, S., Boven, L.A., Laman, J.D., Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J. Pathol. 217 (2009), 543–551.
223. Vargas, T., Ugalde, C., Spuch, C., Antequera, D., Morán, M.J., Martín, M.A., Ferrer, I., Bermejo-Pareja, F., Carro, E., Abeta accumulation in choroid plexus is associated with mitochondrial-induced apoptosis. Neurobiol. Aging 31 (2010), 1569–1581.
224. Vigl, B., Aebischer, D., Nitschké, M., Iolyeva, M., Röthlin, T., Antsiferova, O., Halin, C., Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118 (2011), 205–215.
225. Villeda, S.A., Luo, J., Mosher, K.I., Zou, B., Britschgi, M., Bieri, G., Stan, T.M., Fainberg, N., Ding, Z., Eggel, A., et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477 (2011), 90–94.
226. Vittet, D., Lymphatic collecting vessel maturation and valve morphogenesis. Microvasc. Res. 96 (2014), 31–37.
227. von der Weid, P.-Y., Zawieja, D.C., Lymphatic smooth muscle: the motor unit of lymph drainage. Int. J. Biochem. Cell Biol. 36 (2004), 1147–1153.
228. Voskuhl, R.R., Farris, R.W. 2nd, Nagasato, K., McFarland, H.F., Dalcq, M.D., Epitope spreading occurs in active but not passive EAE induced by myelin basic protein. J. Neuroimmunol. 70 (1996), 103–111.
229. Walker-Caulfield, M.E., Hatfield, J.K., Brown, M.A., Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis. J. Neuroimmunol. 278 (2015), 112–122.
230. Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., Selkoe, D.J., Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416 (2002), 535–539.
231. Wang, Y., Oliver, G., Current views on the function of the lymphatic vasculature in health and disease. Genes Dev. 24 (2010), 2115–2126.
232. Wang, Y., Cella, M., Mallinson, K., Ulrich, J.D., Young, K.L., Robinette, M.L., Gilfillan, S., Krishnan, G.M., Sudhakar, S., Zinselmeyer, B.H., et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160 (2015), 1061–1071.
233. Weber, M., Hauschild, R., Schwarz, J., Moussion, C., de Vries, I., Legler, D.F., Luther, S.A., Bollenbach, T., Sixt, M., Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339 (2013), 328–332.
234. Weiner, H.L., Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch. Neurol. 61 (2004), 1613–1615.
235. Weiss, R., Lifshitz, V., Frenkel, D., TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis. Brain Behav. Immun. 25 (2011), 1017–1024.
236. Weller, R.O., Subash, M., Preston, S.D., Mazanti, I., Carare, R.O., Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 18 (2008), 253–266.
237. Wick, N., Haluza, D., Gurnhofer, E., Raab, I., Kasimir, M.-T., Prinz, M., Steiner, C.-W., Reinisch, C., Howorka, A., Giovanoli, P., et al. Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am. J. Pathol. 173 (2008), 1202–1209.
238. Wolburg, H., Paulus, W., Choroid plexus: biology and pathology. Acta Neuropathol. 119 (2010), 75–88.
239. Wong, A.D., Ye, M., Levy, A.F., Rothstein, J.D., Bergles, D.E., Searson, P.C., The blood-brain barrier: an engineering perspective. Front. Neuroeng., 6, 2013, 7.
240. Wu, J.W., Breydo, L., Isas, J.M., Lee, J., Kuznetsov, Y.G., Langen, R., Glabe, C., Fibrillar oligomers nucleate the oligomerization of monomeric amyloid beta but do not seed fibril formation. J. Biol. Chem. 285 (2010), 6071–6079.
241. Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., Mucke, L., Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature 389 (1997), 603–606.
242. Wyss-Coray, T., Lin, C., Yan, F., Yu, G.Q., Rohde, M., McConlogue, L., Masliah, E., Mucke, L., TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med. 7 (2001), 612–618.
243. Wyss-Coray, T., Loike, J.D., Brionne, T.C., Lu, E., Anankov, R., Yan, F., Silverstein, S.C., Husemann, J., Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 9 (2003), 453–457.
244. Xie, L., Kang, H., Xu, Q., Chen, M.J., Liao, Y., Thiyagarajan, M., O'Donnell, J., Christensen, D.J., Nicholson, C., Iliff, J.J., et al. Sleep drives metabolite clearance from the adult brain. Science 342 (2013), 373–377.
245. Xu, Y., Yuan, L., Mak, J., Pardanaud, L., Caunt, M., Kasman, I., Larrivée, B., Del Toro, R., Suchting, S., Medvinsky, A., et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J. Cell Biol. 188 (2010), 115–130.
246. Xu, Z., Xiao, N., Chen, Y., Huang, H., Marshall, C., Gao, J., Cai, Z., Wu, T., Hu, G., Xiao, M., Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol. Neurodegener., 10, 2015, 58.
247. Yednock, T.A., Cannon, C., Fritz, L.C., Sanchez-Madrid, F., Steinman, L., Karin, N., Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356 (1992), 63–66.
248. Yokoyama, J.S., Wang, Y., Schork, A.J., Thompson, W.K., Karch, C.M., Cruchaga, C., McEvoy, L.K., Witoelar, A., Chen, C.-H., Holland, D., et al., Alzheimer's Disease Neuroimaging Initiative. Association between genetic traits for immune-mediated diseases and Alzheimer disease. JAMA Neurol 73 (2016), 691–697.
249. Zawieja, D.C., von der Weid, P.-Y., Gashev, A.A., Microlymphatic biology. Terjung, R., (eds.) Comprehensive Physiology, 2011, John Wiley & Sons, Inc., 125–158.
250. Zhao, Z., Sagare, A.P., Ma, Q., Halliday, M.R., Kong, P., Kisler, K., Winkler, E.A., Ramanathan, A., Kanekiyo, T., Bu, G., et al. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18 (2015), 978–987.
251. Zlokovic, B.V., Clearing amyloid through the blood-brain barrier. J. Neurochem. 89 (2004), 807–811.
252. Zlokovic, B.V., The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57 (2008), 178–201.
253. Zlokovic, B.V., Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 70 (2013), 440–444.
254. Zlokovic, B.V., Martel, C.L., Matsubara, E., McComb, J.G., Zheng, G., McCluskey, R.T., Frangione, B., Ghiso, J., Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc. Natl. Acad. Sci. USA 93 (1996), 4229–4234.