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Cited by 244Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

Neurovascular Unit Dysfunction and Neurodegenerative Disorders

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Yu, Xing, Ji, Caihong, Shao, Anwen·2020·Frontiers in Neuroscience
DOI 10.3389/fnins.2020.00334PMC PMC7201055
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Abstract

The neurovascular unit (NVU), composed of vascular cells, glial cells, and neurons, is the minimal functional unit of the brain. The NVU maintains integrity of the blood-brain barrier (BBB) and regulates supply of the cerebral blood flow (CBF), both of which are keys to maintaining normal brain function. BBB dysfunction and a decreased CBF are early pathophysiological changes in neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In this review, we primarily focus on the NVU in AD as much research has been performed on the connection between NVU dysfunction and AD. We also discuss the role of NVU dysfunction in the pathophysiological mechanisms of PD and ALS. As most neurodegenerative diseases are difficult to treat, we discuss several potential drug targets that focus on the NVU that may inform novel vascular-targeted therapies for AD, PD, and ALS.

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  1. Agarwal R. Shukla G. S. (1999). Potential role of cerebral glutathione in the maintenance of blood-brain barrier integrity in rat. Neurochem. Res. 24 1507– 1514. 10591399
  2. Alexopoulos P. Sorg C. Forschler A. Grimmer T. Skokou M. Wohlschlager A. (2012). Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI. Eur. Arch. Psychiatry Clin. Neurosci. 262 69– 77. 10.1007/s00406-011-0226-2 21786091 · DOI
  3. Baloyannis S. J. Baloyannis I. S. (2012). The vascular factor in Alzheimer’s disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322 117– 121. 10.1016/j.jns.2012.07.010 22857991 · DOI · Paper page
  4. Bartels A. L. (2011). Blood-brain barrier P-glycoprotein function in neurodegenerative disease. Curr. Pharm. Des 17 2771– 2777. 10.2174/138161211797440122 21831040 · DOI
  5. Binnewijzend M. A. Benedictus M. R. Kuijer J. P. Van Der Flier W. M. Teunissen C. E. Prins N. D. (2016). Cerebral perfusion in the predementia stages of Alzheimer’s disease. Eur. Radiol. 26 506– 514. 10.1007/s00330-015-3834-9 26040647 PMC4712243 · DOI
  6. Biron K. E. Dickstein D. L. Gopaul R. Fenninger F. Jefferies W. A. (2013). Cessation of neoangiogenesis in Alzheimer’s disease follows amyloid-beta immunization. Sci. Rep. 3 1354– 1354. 23446889 PMC3584312
  7. Cabezas R. Avila M. Gonzalez J. El-Bacha R. S. Baez E. Garcia-Segura L. M. (2014). Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front. Cell Neurosci. 8: 211. 10.3389/fncel.2014.00211 25136294 PMC4120694 · DOI
  8. Candela P. Saint-Pol J. Kuntz M. Boucau M. C. Lamartiniere Y. Gosselet F. (2015). In vitro discrimination of the role of LRP1 at the BBB cellular level: focus on brain capillary endothelial cells and brain pericytes. Brain Res. 1594 15– 26. 10.1016/j.brainres.2014.10.047 25451130 · DOI
  9. Carvey P. M. Zhao C. H. Hendey B. Lum H. Trachtenberg J. Desai B. S. (2005). 6-Hydroxydopamine-induced alterations in blood-brain barrier permeability. Eur. J. Neurosci. 22 1158– 1168. 10.1111/j.1460-9568.2005.04281.x 16176358 · DOI · Paper page
  10. Collins L. M. Toulouse A. Connor T. J. Nolan Y. M. (2012). Contributions of central and systemic inflammation to the pathophysiology of Parkinson’s disease. Neuropharmacology 62 2154– 2168. 10.1016/j.neuropharm.2012.01.028 22361232 · DOI · Paper page
  11. Cupino T. L. Zabel M. K. (2014). Alzheimer’s silent partner: cerebral amyloid angiopathy. Translat. Stroke Res. 5 330– 337. 10.1007/s12975-013-0309-7 24323728 · DOI
  12. Daneman R. Zhou L. Kebede A. A. Barres B. A. (2010). Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468 562– 566. 10.1038/nature09513 20944625 PMC3241506 · DOI · Paper page
  13. De La Torre J. C. (1997). Hemodynamic consequences of deformed microvessels in the brain in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 826 75– 91. 10.1111/j.1749-6632.1997.tb48462.x 9329682 · DOI
  14. Dong S. Maniar S. Manole M. D. Sun D. (2018). Cerebral hypoperfusion and other shared brain pathologies in ischemic stroke and Alzheimer’s Disease. Transl. Stroke Res. 9 238– 250. 10.1007/s12975-017-0570-2 28971348 PMC9732865 · DOI
  15. Garbuzova-Davis S. Rodrigues M. C. Hernandez-Ontiveros D. G. Louis M. K. Willing A. E. Borlongan C. V. (2011). Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398 113– 125. 21632035
  16. Garbuzova-Davis S. Saporta S. Haller E. Kolomey I. Bennett S. P. Potter H. (2007). Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One 2: e1205. 10.1371/journal.pone.0001205 18030339 PMC2075163 · DOI
  17. Garbuzova-Davis S. Saporta S. Sanberg P. R. (2008). Implications of blood-brain barrier disruption in ALS. Amyotrophic Lateral Scler. 9 375– 376. 10.1080/17482960802160990 18608097 · DOI
  18. Gordon G. R. Howarth C. Macvicar B. A. (2011). Bidirectional control of arteriole diameter by astrocytes. Exp. Physiol. 96 393– 399. 10.1113/expphysiol.2010.053132 21257665 · DOI
  19. Goulay R. Mena Romo L. Hol E. M. Dijkhuizen R. M. (2019). From stroke to dementia: a comprehensive review exposing tight interactions between stroke and Amyloid-β formation. Translat. Stroke Res. 10.1007/s12975-019-00755-2 [Epub ahead of print]. 31776837 PMC7340665 · DOI
  20. Govindpani K. Mcnamara L. G. Smith N. R. Vinnakota C. Waldvogel H. J. Faull R. L. (2019). Vascular dysfunction in alzheimer’s disease: a prelude to the pathological process or a consequence of it? J. Clin. Med. 8: 8050651. PMC6571853 31083442
  21. Gupta A. Iadecola C. (2015). Impaired Aβ clearance: a potential link between atherosclerosis and Alzheimer’s disease. Front. Aging Neurosci. 7: 115. 10.3389/fncel.2014.00115 26136682 PMC4468824 · DOI
  22. Hamel E. (2004). Cholinergic modulation of the cortical microvascular bed. Prog. Brain Res. 145 171– 178. 10.1016/s0079-6123(03)45012-7 14650915 · DOI
  23. Hamilton N. B. Attwell D. Hall C. N. (2010). Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenerget. 2: 5 10.3389/fnene.2010.00005 PMC2912025 20725515 · DOI · Paper page
  24. Henkel J. S. Beers D. R. Wen S. Bowser R. Appel S. H. (2009). Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology 72 1614– 1616. 10.1212/wnl.0b013e3181a41228 19414730 · DOI · Paper page
  25. Hunter J. M. Kwan J. Malek-Ahmadi M. Maarouf C. L. Kokjohn T. A. Belden C. (2012). Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer’s disease. PLoS One 7: e036893 10.1371/journal.pone.00036893 PMC3353981 22615835 · DOI
  26. Jangula A. Murphy E. J. (2013). Lipopolysaccharide-induced blood brain barrier permeability is enhanced by alpha-synuclein expression. Neurosci. Lett. 551 23– 27. 10.1016/j.neulet.2013.06.058 23876253 PMC3799901 · DOI
  27. Kook S. Y. Hong H. S. Moon M. Ha C. M. Chang S. Mook-Jung I. (2012). Abeta(1)(-)(4)(2)-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca(2)(+)-calcineurin signaling. J. Neurosci. 32 8845– 8854. 10.1523/jneurosci.6102-11.2012 22745485 PMC6622350 · DOI
  28. Kortekaas R. Leenders K. L. Van Oostrom J. C. H. Vaalburg W. Bart J. Willemsen A. T. M. (2005). Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57 176– 179. 10.1002/ana.20369 15668963 · DOI · Paper page
  29. Lee H. Pienaar I. S. (2014). Disruption of the blood-brain barrier in Parkinson’s disease: curse or route to a cure? Front. Biosci. 19: 280 10.3389/fnene.2010.280 24389183 · DOI
  30. Li H. Guo Q. Inoue T. Polito V. A. Tabuchi K. Hammer R. E. (2014). Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol. Neurodegen. 9: 28. 10.1186/1750-1326-9-28 25108425 PMC4132280 · DOI · Paper page
  31. Li L. Zhang X. Yang D. Luo G. Chen S. Le W. (2009). Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol. Aging 30 1091– 1098. 10.1016/j.neurobiolaging.2007.10.011 18063223 · DOI
  32. Liu X. Hou D. Lin F. Luo J. Xie J. Wang Y. (2019). The role of neurovascular unit damage in the occurrence and development of Alzheimer’s disease. Rev. Neurosci. 30 477– 484. 10.1515/revneuro-2018-0056 30530893 · DOI
  33. Loane C. Wu K. Bain P. Brooks D. J. Piccini P. Politis M. (2013). Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD. Neurology 80 1850– 1855. 10.1212/wnl.0b013e318292a31d 23596065 PMC3908354 · DOI
  34. Marco S. Skaper S. D. (2006). Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells. Neurosci. Lett. 401 219– 224. 10.1016/j.neulet.2006.03.047 16644119 · DOI
  35. Masliah E. Hansen L. Adame A. Crews L. Bard F. Lee C. (2005). Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64 129– 131. 10.1212/01.wnl.0000148590.39911.df 15642916 · DOI
  36. Mawuenyega K. G. Sigurdson W. Ovod V. Munsell L. Kasten T. Morris J. C. (2010). Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330: 1774. 10.1126/science.1197623 21148344 PMC3073454 · DOI · Paper page
  37. McColgan P. Tabrizi S. J. (2018). Huntington’s disease: a clinical review. Eur. J. Neurol. 25 24– 34. 28817209
  38. Miller M. C. Tavares R. Johanson C. E. Hovanesian V. Donahue J. E. Gonzalez L. (2008). Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease. Brain Res. 1230 273– 280. 10.1016/j.brainres.2008.06.124 18657529 PMC2585053 · DOI · Paper page
  39. Miyazaki K. Ohta Y. Nagai M. Morimoto N. Kurata T. Takehisa Y. (2011). Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89 718– 728. 10.1002/jnr.22594 21337372 · DOI · Paper page
  40. Mosconi L. (2005). Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur. J. Nucl. Med. Mol. Imaging 32 486– 510. 10.1007/s00259-005-1762-7 15747152 · DOI
  41. Niwa K. Carlson G. A. Iadecola C. (2000). Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J. Cereb. Blood Flow Metab. 20 1659– 1668. 10.1097/00004647-200012000-00005 11129782 · DOI · Paper page
  42. Okamoto Y. Yamamoto T. Kalaria R. N. Senzaki H. Maki T. Hase Y. (2012). Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 123 381– 394. 10.1007/s00401-011-0925-9 22170742 PMC3282897 · DOI · Paper page
  43. Patel P. Shah J. (2017). Role of Vitamin D in Amyloid clearance via LRP-1 upregulation in Alzheimer’s disease: a potential therapeutic target? J. Chem. Neuroanat. 85 36– 42. 10.1016/j.jchemneu.2017.06.007 28669880 · DOI
  44. Pflanzner T. Janko M. C. Andre-Dohmen B. Reuss S. Weggen S. Roebroek A. J. (2011). LRP1 mediates bidirectional transcytosis of amyloid-beta across the blood-brain barrier. Neurobiol. Aging 32 2323– 2311. 20630619
  45. Pienaar I. S. Van De Berg W. (2013). A non-cholinergic neuronal loss in the pedunculopontine nucleus of toxin-evoked parkinsonian rats. Exp. Neurol. 248 213– 223. 10.1016/j.expneurol.2013.06.008 23769975 · DOI
  46. Roberts K. F. Elbert D. L. Kasten T. P. Patterson B. W. Sigurdson W. C. Connors R. E. (2014). Amyloid-β efflux from the central nervous system into the plasma. Ann. Neurol. 76 837– 844. 10.1002/ana.24270 25205593 PMC4355962 · DOI
  47. Schinkel A. H. (1999). P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36 179– 194. 10.1016/s0169-409x(98)00085-4 10837715 · DOI
  48. Schuff N. Matsumoto S. Kmiecik J. Studholme C. Du A. Ezekiel F. (2009). Cerebral blood flow in ischemic vascular dementia and Alzheimer’s disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement. 5 454– 462. 10.1016/j.jalz.2009.04.1233 19896584 PMC2802181 · DOI
  49. Shimizu S. Kanetaka H. Hirose D. Sakurai H. Hanyu H. (2015). Differential effects of acetylcholinesterase inhibitors on clinical responses and cerebral blood flow changes in patients with Alzheimer’s disease: a 12-month, randomized, and open-label trial. Dement. Geriatr. Cogn. Disord. Extra 5 135– 146. 10.1159/000375527 25999980 PMC4439833 · DOI
  50. Shinohara M. Sato N. Kurinami H. Takeuchi D. Takeda S. Shimamura M. (2010). Reduction of brain beta-amyloid (Abeta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Abeta clearance. J. Biol. Chem. 285 22091– 22102. 10.1074/jbc.m110.102277 20472556 PMC2903370 · DOI
  51. Spuch C. Antequera D. Portero A. Orive G. Hernández R. M. Molina J. A. (2010). The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease. Biomaterials 31 5608– 5618. 10.1016/j.biomaterials.2010.03.042 20430437 · DOI
  52. Sweeney M. D. Kisler K. Montagne A. Toga A. W. Zlokovic B. V. (2018). The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci. 21 1318– 1331. 10.1038/s41593-018-0234-x 30250261 PMC6198802 · DOI · Paper page
  53. Thomas T. Thomas G. Mclendon C. Sutton T. Mullan M. (1996). beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380 168– 171. 10.1038/380168a0 8600393 · DOI · Paper page
  54. Tietz S. Engelhardt B. (2015). Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209 493– 506. 10.1083/jcb.201412147 26008742 PMC4442813 · DOI · Paper page
  55. Van Beek A. H. Claassen J. A. (2011). The cerebrovascular role of the cholinergic neural system in Alzheimer’s disease. Behav. Brain Res. 221 537– 542. 10.1016/j.bbr.2009.12.047 20060023 · DOI
  56. Vinters H. V. (2015). Emerging concepts in Alzheimer’s disease. Annu. Rev. Pathol. 10 291– 319. 25387055
  57. Wan W. Cao L. Liu L. Zhang C. Kalionis B. Tai X. (2015). Abeta(1-42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins. J. Neurochem. 134 382– 393. 10.1111/jnc.13122 25866188 · DOI
  58. Whitfield J. F. (2007). The road to LOAD: late-onset Alzheimer’s disease and a possible way to block it. Expert Opin. Ther. Targets 11 1257– 1260. 10.1517/14728222.11.10.1257 17907956 · DOI
  59. Winkler E. A. Bell R. D. Zlokovic B. V. (2011). Central nervous system pericytes in health and disease. Nat. Neurosci. 14 1398– 1405. 10.1038/nn.2946 22030551 PMC4020628 · DOI · Paper page
  60. Zenaro E. Piacentino G. Constantin G. (2017). The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 107 41– 56. 27425887 PMC5600438
  61. Zetterberg H. Mörtberg E. Song L. Chang L. Provuncher G. K. Patel P. P. (2011). Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 6: e028263 10.1371/journal.pone.00028263 PMC3237426 22194817 · DOI
  62. Zhang S. Zhi Y. Li F. Huang S. Gao H. Han Z. (2018). Transplantation of in vitro cultured endothelial progenitor cells repairs the blood-brain barrier and improves cognitive function of APP/PS1 transgenic AD mice. J. Neurol. Sci. 387 6– 15. 10.1016/j.jns.2018.01.019 29571873 · DOI
  63. Zipser B. D. Johanson C. E. Gonzalez L. Berzin T. M. Tavares R. Hulette C. M. (2007). Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol. Aging 28 977– 986. 16782234

Cited by

Sorted by citations

Authors
Yu, X., Ji, C., & Shao, A.
Affiliations
  • Second Affiliated Hospital of Zhejiang University (CN)
  • First Affiliated Hospital Zhejiang University (CN)
Corresponding author
Shao, Anwen
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2020-04-29
Volume
14
Pages
334-334
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2020.00334
PMC
PMC7201055
OpenAlex
W3021983830
Cited by
244
References
19
Citations by year
2026: 35 · 2025: 47 · 2024: 48 · 2023: 43 · 2022: 41 · 2021: 21 · 2020: 9
FWCI
2.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China
  • Natural Science Foundation of Zhejiang Province
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
neurovascular unit, neurodegenerative diseases, blood-brain barrier dysfunction, cerebral blood flow, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, vascular-targeted therapy, therapeutic target, glial cells, vascular cells

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