Central nervous system immunity in relation to aging and AD
Main Article Content
Abstract
The present report discusses the immune and clearance system of the central nervous system (CNS) in terms of its anatomical, physiological, and biochemical properties. There is now a growing body of evidence that progressive dysfunction of the meningeal lymphatic system should be considered as a risk factor for aging-related brain disorders. In addition, the activity of meningeal lymphatics may alter the access of CSF-carried immune neuromodulators to brain parenchyma, which is also involved in the onset of aging and AD. In the CNS clearance system, impairment of the BBB and small arteries, as well as the major protein of the end feet of astrocytes, AQP4, are associated with aging or AD. The idea of maximizing brain "waste discharge" as a new preventive or therapeutic target for neurodegenerative diseases in the context of healthy aging has been accepted.
Keywords:
Central nervous system immunity, aging
Article Details
How to Cite
YANG, Chunhui et al.
Central nervous system immunity in relation to aging and AD.
Medical Research Archives, [S.l.], v. 11, n. 8, aug. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3514>. Date accessed: 07 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i8.3514.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Sandro Da Mesquita, Zachary Papadopoulos, Taitea Dykstra, LoganBrase,....... Jonathan Kipnis. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature 2021 May;593(7858):255-260. doi: 10.1038/s41586-021-03489-0. Epub 2021 Apr 28.
2. Sandro Da Mesquita, Antoine Louveau, Jonathan Kipnis. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 2018 (560): 185-191
3. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, and Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015 (523): 337–341. [PubMed: 26030524]
4. Absinta M, Ha S-K, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, and Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. 2017. Elife 6.
5. Sandro Da Mesquita, Zhongxiao Fu, and Jonathan Kipnis.The Meningeal Lymphatic System: A New Player in Neurophysiology. Neuron, 2018 (100), October 24,375-387
6. James T. Walsh, … , Frauke Zipp, Jonathan Kipnis. MHCII-independent CD4 + T cells protect injured CNS neurons via IL-4 .J Clin Invest. 2015;125(2):699-714. https://doi.org/10.1172/JCI76210
7. Zachary Papadopoulos, Jasmin Herz, Jonathan Kipnis. Meningeal lymphatics: From anatomy to CNS immune surveillance. J Immunol. 2020 January 15; 204(2): 286–293. doi:10.4049/jimmunol.1900838.
8. Noel C. Derecki, Amber N. Cardani, Chunhui Yang, Kayla M. Quinnies, Anastasia Crihfield, Kevin R. Lynch, and Jonathan Kipnis. Regulation of learning and memory by meningeal immunity: a key role for IL-4. JEM. 2010; vol.207, No.5, pp1067-1080
9. Walsh JT, Zheng J, Smirnov I, Lorenz U, Tung K, and Kipnis J. 2014 Regulatory T cells in central nervous system injury: a double-edged sword. J. Immunol. 2014 (193): 5013–5022. [PubMed: 25320276]
10. Jefferson W. Kinney, Shane M. Bemiller, Andrew S. Murtishaw, Amanda M. Leisgang, Arnold M. Salazar, Bruce T. Lamb. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2018(4): 575-590
11. Nicholas C. Cullen, A nders Mälarstig, Erik Stomrud, Oskar Hansson & Niklas Mattsson Carlgren. Accelerated infammatory aging inAlzheimer’s disease and its relation to amyloid, tau, and cognition. Scientifc Reports. 2021 (11). :1965. https://doi.org/10.1038/s41598-021-81705-7
12. Helene Benvenistea, Xiaodan Liu, Sunil Koundala, Simon Sanggaarda, Hedok Leea, Joanna Wardlawc. The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 2019 (65):106–119. DOI: 10.1159/000490349
13. Kevin N. Hascup , Mackenzie R. Peck , Yimin Fang , Nahayo Esperant-Hilaire , Caleigh A. Findley , Samuel McFadden, Andrzej Bartke , Erin R. Hascup. Cellular senescence, inflammation, and cognition in aging and Alzheimer’s disease: What’s the connection? Alzheimer’s Dement. 2021 (17): Suppl.3:e055688. https://doi.org/10.1002/alz.055688
14. Holly Oakley, Sarah L. Cole, Sreemathi Logan, Erika Maus, Pei Shao, Jeffery Craft, Angela Guillozet-Bongaarts, Masuo Ohno, John Disterhoft, Linda Van Eldik, Robert Berry, and Robert Vassar. Intraneuronal -Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer’s Disease Mutations: Potential Factors in Amyloid Plaque Formation. The Journal of Neuroscience. 2006:26(40):10129 –10140
15. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, and Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 2015 (212): 991–999. [PubMed: 26077718]
16. Eide PK, Vatnehol SAS, Emblem KE, and Ringstad G. 2018 Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci. Rep. 2018 (8): 7194. [PubMed: 29740121]
17. Stephen B Hladky and Margery A Barrand. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Hladky and Barrand Fluids and Barriers of the CNS 2014 (11) :26. http://www.fluidsbarrierscns.com/content/11/1/26
18. Cserr HF, Harling-Berg CJ, and Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992 (2): 269–276. [PubMed: 1341962]
19. Hladky SB, and Barrand MA. Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier. Fluids Barriers CNS. 2018 (15): 30. [PubMed: 30340614]
20. Knopf PM, Cserr HF, Nolan SC, Wu TY, and Harling-Berg CJ. Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 1995 (21): 175–180. [PubMed: 7477724]
21. Rua R, and McGavern DB. Advances in meningeal immunity. Trends Mol. Med 2018 (24): 542–559. [PubMed: 29731353]
22. Patrick L. McGeer and Edith G. McGeer. Innate Immunity, Local Inflammation, and Degenerative Disease. www.sageke.sciencemag.org/cgi/content/full/sageke;2002/29/re3
23. Alex J. Smith, Tianjiao Duan. Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer’s disease by remodeling periplaque astrocyte structure. Acta Neuropathologica Coummunications, 2019, 7(74)
24. Simone Mader, and Lior Brimberg. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019, 8, 90; doi:10.3390/cells8020090. www.mdpi.com/journal/cells
25. Xu, Z. et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol. Neurodegener. 2015 (10):58
26. Zeppenfeld, D. M. et al. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 2017 (74):91-99
27. Akihiko Hoshi, Teiji Yamamoto, Keiko Shimizu, Yoshikazu Ugawa, Masatoyo Nishizawa, Hitoshi Takahashi, and Akiyoshi Kakita . Characteristics of Aquaporin Expression Surrounding Senile Plaques and Cerebral Amyloid Angiopathy in Alzheimer Disease. J Neuropathol Exp Neurol.2012 Volume 71, Number 8, August 750- 759
28. Danica B Stanimirovic and Alon Friedman. Pathophysiology of the neurovascular unit: disease cause or consequence? Journal of Cerebral Blood Flow & Metabolism 2012 (32):1207-1221
29. HeatherL.McConnell, CymonN.Kersch, RandallL.Woltjer, and EdwardA. Neuwelt. TheTranslational Significance of the Neurovascular Unit. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 2017, 292, NO. 3, pp. 762–770
30. Julie A. Schneider, Zoe Arvanitakis, Woojeong Bang, David A. Bennett. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007; 69 (24), 2197-2204
31. Julie A. Schneider and David A. Bennett. Where Vascular Meets Neurodegenerative Disease. Stroke. 2010 (41), Issue 10_suppl_1, 1 October 2010; Pages S144-S146. https://doi.org/10.1161/STROKEAHA.110.598326
32. Howard A. Crystal, Julie A. Schneider, David A. Bennett, Sue Leurgans, and Steven R. Levine. Associations of Cerebrovascular and Alzheimer’s Disease Pathology with Brain Atrophy. Curr Alzheimer Res. 2014; 11(4): 309–316
33. M. Brandon, Matt T. Bianchi, Chunhui Yang, Julie A Schneider, Steven M. Greenberg. Estimating cerebral microinfarct burden from autopsy samples. Neurology. 2013; 80: 1365-1369
34. Melissa Lamar, Sue Leurgans, Alifiya Kapasi, Lisa L Barnes, Patricia A Boyle, David A Bennett, Konstantinos Arfanakis, Julie A Schneider. Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship with Cognitive Decline. Stroke. 2022;53(1):218-227. doi:10.1161/STROKEAHA.121.034814. Epub 2021 Oct 4.
35. Annie J. Lee, Neha S. Raghavan, Prabesh Bhattarai, Tohid Siddiqui, Sanjeev Sariya, Dolly Reyes-Dumeyer, Xena E. Flowers, Sarah A. L. Cardoso, Philip L. De Jager, David A. Bennett, Julie A. Schneider, Vilas Menon, Yanling Wang, Rafael A. Lantigua, Martin Medrano, Diones Rivera, Ivonne Z. Jiménez-Velázquez, Walter A. Kukull, Adam M. Brickman, Jennifer J. Manly, Giuseppe Tosto, Caghan Kizil, Badri N. Vardarajan, Richard Mayeux. FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease. Acta Neuropathologica, 2022; DOI: 10.1007/s00401-022-02431-6
36. Ajami B, Samusik N, Wieghofer P, Ho PP, Crotti A, Bjornson Z, Prinz M, Fantl WJ, Nolan GP, and Steinman L. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 2018; 21: 541–551. [PubMed: 29507414]
37. McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, and Griffin B. Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res. 2003. 313: 259– 269. [PubMed: 12920643]
38. Dando SJ, Kazanis R, Chinnery HR, and McMenamin PG. Regional and functional heterogeneity of antigen presenting cells in the mouse brain and meninges. Glia.2019 (67): 935–949. [PubMed: 30585356]
39. Gabor G. Kovacs, Sharon X. Xie, John L. Robinson, Edward B. Lee, Douglas H. Smith, Theresa Schuck, Virginia M.-Y. Lee and John Q. Trojanowski. Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain.Acta Neuropathologica Communications. 2018; 6:50. https://doi.org/10.1186/s40478-018-0552-y
40. Zhao, Z. et al. Central role for PICALM in amyloid-β blood–brain barrier transcytosis and clearance. Nat. Neurosci. 2015(18):978-987
41. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 2012(4):147ra111
42. Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 2014(76):845-861
43. Peng, W. et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 2016(93):215-225
44. Richard, B. C. et al. Gene dosage dependent aggravation of the neurological phenotype in the 5XFAD mouse model of Alzheimer’s disease. J. Alzheimers Dis. 2015(45):1223-1236
45. Antoine Louveau et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.J Clin Invest. 2017
46. Ryota Tamura et al. Current understanding of lymphatic vessels in the central nervous system. Neurosurg Rev. 2020; 43(4):1055-1064
47. Jonathan Kipnis. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016; 353 (6301):766-71. doi:10.1126/science.aag2638
48. Jonathan Kipnis et al. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA 2004; 101 (21):8180-5. doi:10.1073/pnas.0402268101.
49. Fabio Bucchieri et al. Lymphatic vessels of the dura mater: a new discovery? J Anat.2015; 227 (5):702-3. doi:10.1111/joa.12381.
50. R Daneman and Alexandre Prat. The Blood-Brain Barreer. Cold Spring Harbor Perpectives in Biology. 2015; 7 (1): a02412. http://cshperspectives.org
51. Gloria B Choi et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016; 351(6276):933-9. doi:10.1126/science.aad0314
52. Christina F Voglaar.......Jonathan Kipnis et al. Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. Sci Transl Med. 2018; 10(430):eaao2304. dio:10.1126/scitranslmed.aao2304
53. Anthony J Filiano...... Jonathan Kipnis. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016; 535(7612):425-9. doi:10.1038/nature18626
54. Burkhard Becher, Sabine Spath, Joan Goverman. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017; 17 (1):49-59. doi:10.1038/nri.2016.123.
55. Schin P Gadani, James T Walsh, Igor Smirnov, Jingjing Zheng, Jonathan Kipnis. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron. 2015; 85 (4):703-9. doi:10.1016/j.neuron.2015.01.013
56. David Stellwagen, Robert C Malenka. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006; 440 (7087):1054-9. doi:10.1038/nature04671
57. Georg Gasteiger, Alexander Y Rudensky. Interaction between innate and adaptive lymphocytes. Na Rev Immunol. 2014; 14 (9):631-9. doi:10.1038/nri3726
58. Juan Maurico Garre et al. CX3CR1 monocytes modulate learning and learning-dependant dendritic spine remodeling via TNF-α. Nat Med. 2017; 23 (6):714-722. doi:10.1038/nm.4340
59. Hadas Keren-Shaul et al. A unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017; 169 (7):1276-1290.e17. doi: 10.1016/j.cell.2017.05.018.
60. Ron Brookmeyer et al. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2018; 14 (2): 121-129. doi:10.1016/j.jalz.2017.10.009.
61. Jenna M Tarasoff-Conway et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2016; 12 (4):248. doi:10.1038/nrneurol.2016.36.
62. B V Zlokovic. Cerebrovascular transport of Alzheimer’s amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 1996; 59 (18): 1483-97. doi:10.1016/0024-3205(96)00310-4.
63. Mahdi Asgari, Diane de Zelicourt & Vartan Kurtcuoglu. Glymphatic solute transport does not require bulk flow. Scientific Reports. 2016; 6:38635. doi:10.1038/srep38635
64. Antoine Louveau, Igor Smirnov, [……], and Jonathan Kipnis. Structural and functional features of central nervous system lymphatics. Nature. 2015; 523(7560): 337-341
2. Sandro Da Mesquita, Antoine Louveau, Jonathan Kipnis. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 2018 (560): 185-191
3. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, and Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015 (523): 337–341. [PubMed: 26030524]
4. Absinta M, Ha S-K, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, and Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. 2017. Elife 6.
5. Sandro Da Mesquita, Zhongxiao Fu, and Jonathan Kipnis.The Meningeal Lymphatic System: A New Player in Neurophysiology. Neuron, 2018 (100), October 24,375-387
6. James T. Walsh, … , Frauke Zipp, Jonathan Kipnis. MHCII-independent CD4 + T cells protect injured CNS neurons via IL-4 .J Clin Invest. 2015;125(2):699-714. https://doi.org/10.1172/JCI76210
7. Zachary Papadopoulos, Jasmin Herz, Jonathan Kipnis. Meningeal lymphatics: From anatomy to CNS immune surveillance. J Immunol. 2020 January 15; 204(2): 286–293. doi:10.4049/jimmunol.1900838.
8. Noel C. Derecki, Amber N. Cardani, Chunhui Yang, Kayla M. Quinnies, Anastasia Crihfield, Kevin R. Lynch, and Jonathan Kipnis. Regulation of learning and memory by meningeal immunity: a key role for IL-4. JEM. 2010; vol.207, No.5, pp1067-1080
9. Walsh JT, Zheng J, Smirnov I, Lorenz U, Tung K, and Kipnis J. 2014 Regulatory T cells in central nervous system injury: a double-edged sword. J. Immunol. 2014 (193): 5013–5022. [PubMed: 25320276]
10. Jefferson W. Kinney, Shane M. Bemiller, Andrew S. Murtishaw, Amanda M. Leisgang, Arnold M. Salazar, Bruce T. Lamb. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2018(4): 575-590
11. Nicholas C. Cullen, A nders Mälarstig, Erik Stomrud, Oskar Hansson & Niklas Mattsson Carlgren. Accelerated infammatory aging inAlzheimer’s disease and its relation to amyloid, tau, and cognition. Scientifc Reports. 2021 (11). :1965. https://doi.org/10.1038/s41598-021-81705-7
12. Helene Benvenistea, Xiaodan Liu, Sunil Koundala, Simon Sanggaarda, Hedok Leea, Joanna Wardlawc. The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 2019 (65):106–119. DOI: 10.1159/000490349
13. Kevin N. Hascup , Mackenzie R. Peck , Yimin Fang , Nahayo Esperant-Hilaire , Caleigh A. Findley , Samuel McFadden, Andrzej Bartke , Erin R. Hascup. Cellular senescence, inflammation, and cognition in aging and Alzheimer’s disease: What’s the connection? Alzheimer’s Dement. 2021 (17): Suppl.3:e055688. https://doi.org/10.1002/alz.055688
14. Holly Oakley, Sarah L. Cole, Sreemathi Logan, Erika Maus, Pei Shao, Jeffery Craft, Angela Guillozet-Bongaarts, Masuo Ohno, John Disterhoft, Linda Van Eldik, Robert Berry, and Robert Vassar. Intraneuronal -Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer’s Disease Mutations: Potential Factors in Amyloid Plaque Formation. The Journal of Neuroscience. 2006:26(40):10129 –10140
15. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, and Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 2015 (212): 991–999. [PubMed: 26077718]
16. Eide PK, Vatnehol SAS, Emblem KE, and Ringstad G. 2018 Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci. Rep. 2018 (8): 7194. [PubMed: 29740121]
17. Stephen B Hladky and Margery A Barrand. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Hladky and Barrand Fluids and Barriers of the CNS 2014 (11) :26. http://www.fluidsbarrierscns.com/content/11/1/26
18. Cserr HF, Harling-Berg CJ, and Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992 (2): 269–276. [PubMed: 1341962]
19. Hladky SB, and Barrand MA. Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier. Fluids Barriers CNS. 2018 (15): 30. [PubMed: 30340614]
20. Knopf PM, Cserr HF, Nolan SC, Wu TY, and Harling-Berg CJ. Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 1995 (21): 175–180. [PubMed: 7477724]
21. Rua R, and McGavern DB. Advances in meningeal immunity. Trends Mol. Med 2018 (24): 542–559. [PubMed: 29731353]
22. Patrick L. McGeer and Edith G. McGeer. Innate Immunity, Local Inflammation, and Degenerative Disease. www.sageke.sciencemag.org/cgi/content/full/sageke;2002/29/re3
23. Alex J. Smith, Tianjiao Duan. Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer’s disease by remodeling periplaque astrocyte structure. Acta Neuropathologica Coummunications, 2019, 7(74)
24. Simone Mader, and Lior Brimberg. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019, 8, 90; doi:10.3390/cells8020090. www.mdpi.com/journal/cells
25. Xu, Z. et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol. Neurodegener. 2015 (10):58
26. Zeppenfeld, D. M. et al. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 2017 (74):91-99
27. Akihiko Hoshi, Teiji Yamamoto, Keiko Shimizu, Yoshikazu Ugawa, Masatoyo Nishizawa, Hitoshi Takahashi, and Akiyoshi Kakita . Characteristics of Aquaporin Expression Surrounding Senile Plaques and Cerebral Amyloid Angiopathy in Alzheimer Disease. J Neuropathol Exp Neurol.2012 Volume 71, Number 8, August 750- 759
28. Danica B Stanimirovic and Alon Friedman. Pathophysiology of the neurovascular unit: disease cause or consequence? Journal of Cerebral Blood Flow & Metabolism 2012 (32):1207-1221
29. HeatherL.McConnell, CymonN.Kersch, RandallL.Woltjer, and EdwardA. Neuwelt. TheTranslational Significance of the Neurovascular Unit. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 2017, 292, NO. 3, pp. 762–770
30. Julie A. Schneider, Zoe Arvanitakis, Woojeong Bang, David A. Bennett. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007; 69 (24), 2197-2204
31. Julie A. Schneider and David A. Bennett. Where Vascular Meets Neurodegenerative Disease. Stroke. 2010 (41), Issue 10_suppl_1, 1 October 2010; Pages S144-S146. https://doi.org/10.1161/STROKEAHA.110.598326
32. Howard A. Crystal, Julie A. Schneider, David A. Bennett, Sue Leurgans, and Steven R. Levine. Associations of Cerebrovascular and Alzheimer’s Disease Pathology with Brain Atrophy. Curr Alzheimer Res. 2014; 11(4): 309–316
33. M. Brandon, Matt T. Bianchi, Chunhui Yang, Julie A Schneider, Steven M. Greenberg. Estimating cerebral microinfarct burden from autopsy samples. Neurology. 2013; 80: 1365-1369
34. Melissa Lamar, Sue Leurgans, Alifiya Kapasi, Lisa L Barnes, Patricia A Boyle, David A Bennett, Konstantinos Arfanakis, Julie A Schneider. Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship with Cognitive Decline. Stroke. 2022;53(1):218-227. doi:10.1161/STROKEAHA.121.034814. Epub 2021 Oct 4.
35. Annie J. Lee, Neha S. Raghavan, Prabesh Bhattarai, Tohid Siddiqui, Sanjeev Sariya, Dolly Reyes-Dumeyer, Xena E. Flowers, Sarah A. L. Cardoso, Philip L. De Jager, David A. Bennett, Julie A. Schneider, Vilas Menon, Yanling Wang, Rafael A. Lantigua, Martin Medrano, Diones Rivera, Ivonne Z. Jiménez-Velázquez, Walter A. Kukull, Adam M. Brickman, Jennifer J. Manly, Giuseppe Tosto, Caghan Kizil, Badri N. Vardarajan, Richard Mayeux. FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease. Acta Neuropathologica, 2022; DOI: 10.1007/s00401-022-02431-6
36. Ajami B, Samusik N, Wieghofer P, Ho PP, Crotti A, Bjornson Z, Prinz M, Fantl WJ, Nolan GP, and Steinman L. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 2018; 21: 541–551. [PubMed: 29507414]
37. McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, and Griffin B. Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res. 2003. 313: 259– 269. [PubMed: 12920643]
38. Dando SJ, Kazanis R, Chinnery HR, and McMenamin PG. Regional and functional heterogeneity of antigen presenting cells in the mouse brain and meninges. Glia.2019 (67): 935–949. [PubMed: 30585356]
39. Gabor G. Kovacs, Sharon X. Xie, John L. Robinson, Edward B. Lee, Douglas H. Smith, Theresa Schuck, Virginia M.-Y. Lee and John Q. Trojanowski. Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain.Acta Neuropathologica Communications. 2018; 6:50. https://doi.org/10.1186/s40478-018-0552-y
40. Zhao, Z. et al. Central role for PICALM in amyloid-β blood–brain barrier transcytosis and clearance. Nat. Neurosci. 2015(18):978-987
41. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 2012(4):147ra111
42. Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 2014(76):845-861
43. Peng, W. et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 2016(93):215-225
44. Richard, B. C. et al. Gene dosage dependent aggravation of the neurological phenotype in the 5XFAD mouse model of Alzheimer’s disease. J. Alzheimers Dis. 2015(45):1223-1236
45. Antoine Louveau et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.J Clin Invest. 2017
46. Ryota Tamura et al. Current understanding of lymphatic vessels in the central nervous system. Neurosurg Rev. 2020; 43(4):1055-1064
47. Jonathan Kipnis. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016; 353 (6301):766-71. doi:10.1126/science.aag2638
48. Jonathan Kipnis et al. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA 2004; 101 (21):8180-5. doi:10.1073/pnas.0402268101.
49. Fabio Bucchieri et al. Lymphatic vessels of the dura mater: a new discovery? J Anat.2015; 227 (5):702-3. doi:10.1111/joa.12381.
50. R Daneman and Alexandre Prat. The Blood-Brain Barreer. Cold Spring Harbor Perpectives in Biology. 2015; 7 (1): a02412. http://cshperspectives.org
51. Gloria B Choi et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016; 351(6276):933-9. doi:10.1126/science.aad0314
52. Christina F Voglaar.......Jonathan Kipnis et al. Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. Sci Transl Med. 2018; 10(430):eaao2304. dio:10.1126/scitranslmed.aao2304
53. Anthony J Filiano...... Jonathan Kipnis. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016; 535(7612):425-9. doi:10.1038/nature18626
54. Burkhard Becher, Sabine Spath, Joan Goverman. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017; 17 (1):49-59. doi:10.1038/nri.2016.123.
55. Schin P Gadani, James T Walsh, Igor Smirnov, Jingjing Zheng, Jonathan Kipnis. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron. 2015; 85 (4):703-9. doi:10.1016/j.neuron.2015.01.013
56. David Stellwagen, Robert C Malenka. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006; 440 (7087):1054-9. doi:10.1038/nature04671
57. Georg Gasteiger, Alexander Y Rudensky. Interaction between innate and adaptive lymphocytes. Na Rev Immunol. 2014; 14 (9):631-9. doi:10.1038/nri3726
58. Juan Maurico Garre et al. CX3CR1 monocytes modulate learning and learning-dependant dendritic spine remodeling via TNF-α. Nat Med. 2017; 23 (6):714-722. doi:10.1038/nm.4340
59. Hadas Keren-Shaul et al. A unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017; 169 (7):1276-1290.e17. doi: 10.1016/j.cell.2017.05.018.
60. Ron Brookmeyer et al. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2018; 14 (2): 121-129. doi:10.1016/j.jalz.2017.10.009.
61. Jenna M Tarasoff-Conway et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2016; 12 (4):248. doi:10.1038/nrneurol.2016.36.
62. B V Zlokovic. Cerebrovascular transport of Alzheimer’s amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 1996; 59 (18): 1483-97. doi:10.1016/0024-3205(96)00310-4.
63. Mahdi Asgari, Diane de Zelicourt & Vartan Kurtcuoglu. Glymphatic solute transport does not require bulk flow. Scientific Reports. 2016; 6:38635. doi:10.1038/srep38635
64. Antoine Louveau, Igor Smirnov, [……], and Jonathan Kipnis. Structural and functional features of central nervous system lymphatics. Nature. 2015; 523(7560): 337-341