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The Role of Neurovascular System in Neurodegenerative Diseases

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Abstract

The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain’s microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.

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References

  1. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog Drug Res 61:39–78

    CAS  PubMed  Google Scholar 

  2. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738. https://doi.org/10.1038/nrn3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paredes I, Himmels P, Ruiz de Almodovar C (2018) Neurovascular communication during CNS development. Dev Cell 45(1):10–32. https://doi.org/10.1016/j.devcel.2018.01.023

    Article  CAS  PubMed  Google Scholar 

  4. Lendahl U, Nilsson P, Betsholtz C (2019) Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes. EMBO Rep 20(11):e48070. https://doi.org/10.15252/embr.201948070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282(21):4067–4079. https://doi.org/10.1111/febs.13412

    Article  CAS  PubMed  Google Scholar 

  6. Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV (2016) Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta 1862(5):887–900. https://doi.org/10.1016/j.bbadis.2015.12.016

    Article  CAS  PubMed  Google Scholar 

  7. Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1):a020412. https://doi.org/10.1101/cshperspect.a020412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Geranmayeh MH, Rahbarghazi R, Farhoudi M (2019) Targeting pericytes for neurovascular regeneration. Cell Commun Signal 17(1):26. https://doi.org/10.1186/s12964-019-0340-8

    Article  PubMed  PubMed Central  Google Scholar 

  9. Thanabalasundaram G, Schneidewind J, Pieper C, Galla HJ (2011) The impact of pericytes on the blood-brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol 43(9):1284–1293. https://doi.org/10.1016/j.biocel.2011.05.002

    Article  CAS  PubMed  Google Scholar 

  10. Brown LS, Foster CG, Courtney JM, King NE, Howells DW, Sutherland BA (2019) Pericytes and neurovascular function in the healthy and diseased brain. Front Cell Neurosci 13:282. https://doi.org/10.3389/fncel.2019.00282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19(6):771–783. https://doi.org/10.1038/nn.4288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hladky SB, Barrand MA (2016) Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. Fluids Barriers CNS 13(1):19. https://doi.org/10.1186/s12987-016-0040-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hawkins RA, O'Kane RL, Simpson IA, Vina JR (2006) Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 136(1 Suppl):218S–226S. https://doi.org/10.1093/jn/136.1.218S

    Article  CAS  PubMed  Google Scholar 

  14. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201. https://doi.org/10.1016/j.neuron.2008.01.003

    Article  CAS  PubMed  Google Scholar 

  15. Hashimura T, Kimura T, Miyakawa T (1991) Morphological changes of blood vessels in the brain with Alzheimer’s disease. Jpn J Psychiatry Neurol 45(3):661–665. https://doi.org/10.1111/j.1440-1819.1991.tb01187.x

    Article  CAS  PubMed  Google Scholar 

  16. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118(1):103–113. https://doi.org/10.1007/s00401-009-0522-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab 36(1):216–227. https://doi.org/10.1038/jcbfm.2015.44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deane R, Zlokovic BV (2007) Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 4(2):191–197

    Article  CAS  PubMed  Google Scholar 

  19. Mackic JB, Bading J, Ghiso J, Walker L, Wisniewski T, Frangione B, Zlokovic BV (2002) Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer’s disease lesions. Vascul Pharmacol 38(6):303–313

    Article  CAS  PubMed  Google Scholar 

  20. Montagne A, Zhao Z, Zlokovic BV (2017) Alzheimer’s disease: a matter of blood-brain barrier dysfunction? J Exp Med 214(11):3151–3169. https://doi.org/10.1084/jem.20171406jem.20171406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14(3):133–150. https://doi.org/10.1038/nrneurol.2017.188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18(7):419–434. https://doi.org/10.1038/nrn.2017.48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Leijenaar JF, van Maurik IS, Kuijer JPA, van der Flier WM, Scheltens P, Barkhof F, Prins ND (2017) Lower cerebral blood flow in subjects with Alzheimer’s dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging. Alzheimers Dement (Amst) 9:76–83. https://doi.org/10.1016/j.dadm.2017.10.001

    Article  Google Scholar 

  24. Yu X, Ji C, Shao A (2020) Neurovascular unit dysfunction and neurodegenerative disorders. Front Neurosci 14:334. https://doi.org/10.3389/fnins.2020.00334

    Article  PubMed  PubMed Central  Google Scholar 

  25. Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S et al (2015) GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18(4):521–530. https://doi.org/10.1038/nn.3966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mooradian AD, Chung HC, Shah GN (1997) GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 18(5):469–474

    Article  CAS  PubMed  Google Scholar 

  27. Wang F, Cao Y, Ma L, Pei H, Rausch WD, Li H (2018) Dysfunction of cerebrovascular endothelial cells: prelude to vascular dementia. Front Aging Neurosci 10:376. https://doi.org/10.3389/fnagi.2018.00376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ruiz de Almodovar C, Lambrechts D, Mazzone M, Carmeliet P (2009) Role and therapeutic potential of VEGF in the nervous system. Physiol Rev 89(2):607–648. https://doi.org/10.1152/physrev.00031.2008

    Article  CAS  PubMed  Google Scholar 

  29. Lange C, Storkebaum E, de Almodovar CR, Dewerchin M, Carmeliet P (2016) Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat Rev Neurol 12(8):439–454. https://doi.org/10.1038/nrneurol.2016.88

    Article  CAS  PubMed  Google Scholar 

  30. Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, Kwakowsky A (2019) Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it? J Clin Med 8(5). https://doi.org/10.3390/jcm8050651

  31. Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96(1):17–42. https://doi.org/10.1016/j.neuron.2017.07.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular uncoupling in the triple transgenic model of Alzheimer’s disease: impaired cerebral blood flow response to neuronal-derived nitric oxide signaling. Exp Neurol 291:36–43. https://doi.org/10.1016/j.expneurol.2017.01.013

    Article  CAS  PubMed  Google Scholar 

  33. Zacchigna S, Lambrechts D, Carmeliet P (2008) Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci 9(3):169–181. https://doi.org/10.1038/nrn2336

    Article  CAS  PubMed  Google Scholar 

  34. Uemura MT, Maki T, Ihara M, Lee VMY, Trojanowski JQ (2020) Brain microvascular pericytes in vascular cognitive impairment and dementia. Front Aging Neurosci 12:80. https://doi.org/10.3389/fnagi.2020.00080

    Article  PubMed  PubMed Central  Google Scholar 

  35. Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64(6):575–611. https://doi.org/10.1016/s0301-0082(00)00068-x

    Article  CAS  PubMed  Google Scholar 

  36. Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV (2013) Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 4:2932. https://doi.org/10.1038/ncomms3932

    Article  CAS  PubMed  Google Scholar 

  37. Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS et al (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20(3):406–416. https://doi.org/10.1038/nn.4489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, Kanekiyo T, Holtzman DM et al (2017) Astrocytic LRP1 mediates brain abeta clearance and impacts amyloid deposition. J Neurosci 37(15):4023–4031. https://doi.org/10.1523/JNEUROSCI.3442-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shinohara M, Tachibana M, Kanekiyo T, Bu G (2017) Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res 58(7):1267–1281. https://doi.org/10.1194/jlr.R075796jlr.R075796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tamaki C, Ohtsuki S, Iwatsubo T, Hashimoto T, Yamada K, Yabuki C, Terasaki T (2006) Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid beta-peptide by the liver. Pharm Res 23(7):1407–1416. https://doi.org/10.1007/s11095-006-0208-7

    Article  CAS  PubMed  Google Scholar 

  41. Sagare AP, Deane R, Zetterberg H, Wallin A, Blennow K, Zlokovic BV (2011) Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-beta is an early biomarker for mild cognitive impairment preceding Alzheimer’s disease. J Alzheimers Dis 24(1):25–34. https://doi.org/10.3233/JAD-2010-1012481H1W2L372W21R482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rasmussen MK, Mestre H, Nedergaard M (2018) The glymphatic pathway in neurological disorders. Lancet Neurol 17(11):1016–1024. https://doi.org/10.1016/S1474-4422(18)30318-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Valenza M, Facchinetti R, Steardo L, Scuderi C (2019) Altered waste disposal system in aging and Alzheimer’s disease: focus on astrocytic aquaporin-4. Front Pharmacol 10:1656. https://doi.org/10.3389/fphar.2019.01656

    Article  CAS  PubMed  Google Scholar 

  44. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4(147):147ra111. https://doi.org/10.1126/scitranslmed.3003748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeppenfeld DM, Simon M, Haswell JD, D'Abreo D, Murchison C, Quinn JF, Grafe MR, Woltjer RL et al (2017) Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol 74(1):91–99. https://doi.org/10.1001/jamaneurol.2016.4370

    Article  PubMed  Google Scholar 

  46. Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV (2018) The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21(10):1318–1331. https://doi.org/10.1038/s41593-018-0234-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH (2005) Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57(2):176–179. https://doi.org/10.1002/ana.20369

    Article  CAS  PubMed  Google Scholar 

  48. Ham JH, Yi H, Sunwoo MK, Hong JY, Sohn YH, Lee PH (2014) Cerebral microbleeds in patients with Parkinson’s disease. J Neurol 261(8):1628–1635. https://doi.org/10.1007/s00415-014-7403-y

    Article  PubMed  Google Scholar 

  49. Melzer TR, Watts R, MacAskill MR, Pearson JF, Rueger S, Pitcher TL, Livingston L, Graham C et al (2011) Arterial spin labelling reveals an abnormal cerebral perfusion pattern in Parkinson’s disease. Brain 134(Pt 3):845–855. https://doi.org/10.1093/brain/awq377

    Article  PubMed  PubMed Central  Google Scholar 

  50. Desai BS, Monahan AJ, Carvey PM, Hendey B (2007) Blood-brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy. Cell Transplant 16(3):285–299. https://doi.org/10.3727/000000007783464731

    Article  PubMed  Google Scholar 

  51. Rite I, Machado A, Cano J, Venero JL (2007) Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J Neurochem 101(6):1567–1582. https://doi.org/10.1111/j.1471-4159.2007.04567.x

    Article  CAS  PubMed  Google Scholar 

  52. Masato A, Plotegher N, Boassa D, Bubacco L (2019) Impaired dopamine metabolism in Parkinson’s disease pathogenesis. Mol Neurodegener 14(1):35. https://doi.org/10.1186/s13024-019-0332-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pelizzari L, Lagana MM, Rossetto F, Bergsland N, Galli M, Baselli G, Clerici M, Nemni R et al (2019) Cerebral blood flow and cerebrovascular reactivity correlate with severity of motor symptoms in Parkinson’s disease. Ther Adv Neurol Disord 12:1756286419838354. https://doi.org/10.1177/1756286419838354

    Article  PubMed  PubMed Central  Google Scholar 

  54. Al-Bachari S, Parkes LM, Vidyasagar R, Hanby MF, Tharaken V, Leroi I, Emsley HC (2014) Arterial spin labelling reveals prolonged arterial arrival time in idiopathic Parkinson’s disease. Neuroimage Clin 6:1–8. https://doi.org/10.1016/j.nicl.2014.07.014

    Article  PubMed  PubMed Central  Google Scholar 

  55. Syrimi ZJ, Vojtisek L, Eliasova I, Viskova J, Svatkova A, Vanicek J, Rektorova I (2017) Arterial spin labelling detects posterior cortical hypoperfusion in non-demented patients with Parkinson’s disease. J Neural Transm (Vienna) 124(5):551–557. https://doi.org/10.1007/s00702-017-1703-1

    Article  CAS  Google Scholar 

  56. Pienaar IS, Lee CH, Elson JL, McGuinness L, Gentleman SM, Kalaria RN, Dexter DT (2015) Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson’s disease. Neurobiol Dis 74:392–405. https://doi.org/10.1016/j.nbd.2014.12.006

    Article  PubMed  Google Scholar 

  57. Dohgu S, Takata F, Matsumoto J, Kimura I, Yamauchi A, Kataoka Y (2019) Monomeric alpha-synuclein induces blood-brain barrier dysfunction through activated brain pericytes releasing inflammatory mediators in vitro. Microvasc Res 124:61–66. https://doi.org/10.1016/j.mvr.2019.03.005

    Article  CAS  PubMed  Google Scholar 

  58. Gameiro M, Silva R, Rocha-Pereira C, Carmo H, Carvalho F, Bastos ML, Remiao F (2017) Cellular models and in vitro assays for the screening of modulators of P-gp, MRP1 and BCRP. Molecules 22(4). https://doi.org/10.3390/molecules22040600molecules22040600

  59. Sita G, Hrelia P, Tarozzi A, Morroni F (2017) P-glycoprotein (ABCB1) and oxidative stress: focus on Alzheimer’s disease. Oxid Med Cell Longev 2017:7905486. https://doi.org/10.1155/2017/7905486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wenk GL, Parsons CG, Danysz W (2006) Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol 17(5–6):411–424

    Article  CAS  PubMed  Google Scholar 

  61. Zou W, Pu T, Feng W, Lu M, Zheng Y, Du R, Xiao M, Hu G (2019) Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated alpha-synuclein. Transl Neurodegener 8:7. https://doi.org/10.1186/s40035-019-0147-y

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tamtaji OR, Behnam M, Pourattar MA, Jafarpour H, Asemi Z (2019) Aquaporin 4: a key player in Parkinson’s disease. J Cell Physiol 234(12):21471–21478. https://doi.org/10.1002/jcp.28871

    Article  CAS  PubMed  Google Scholar 

  63. Dong Y, Yuan Y, Fang Y, Zheng T, Du D, Gao D, Du J, Liu L et al (2020) Effect of aquaporin 4 protein overexpression in nigrostriatal system on development of Parkinson's disease. Int J Neurosci:1–8. https://doi.org/10.1080/00207454.2020.1753727

  64. Miyazaki K, Ohta Y, Nagai M, Morimoto N, Kurata T, Takehisa Y, Ikeda Y, Matsuura T et al (2011) Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res 89(5):718–728. https://doi.org/10.1002/jnr.22594

    Article  CAS  PubMed  Google Scholar 

  65. Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O'Banion MK, Stojanovic K, Sagare A et al (2008) ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci 11(4):420–422. https://doi.org/10.1038/nn2073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Garbuzova-Davis S, Sanberg PR (2014) Blood-CNS Barrier Impairment in ALS patients versus an animal model. Front Cell Neurosci 8:21. https://doi.org/10.3389/fncel.2014.00021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125(1):111–120. https://doi.org/10.1007/s00401-012-1039-8

    Article  CAS  PubMed  Google Scholar 

  68. Rodrigues MC, Hernandez-Ontiveros DG, Louis MK, Willing AE, Borlongan CV, Sanberg PR, Voltarelli JC, Garbuzova-Davis S (2012) Neurovascular aspects of amyotrophic lateral sclerosis. Int Rev Neurobiol 102:91–106. https://doi.org/10.1016/B978-0-12-386986-9.00004-1

    Article  CAS  PubMed  Google Scholar 

  69. Henkel JS, Beers DR, Wen S, Bowser R, Appel SH (2009) Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology 72(18):1614–1616. https://doi.org/10.1212/WNL.0b013e3181a41228

    Article  CAS  PubMed  Google Scholar 

  70. Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR (2007) Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One 2(11):e1205. https://doi.org/10.1371/journal.pone.0001205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Garbuzova-Davis S, Rodrigues MC, Hernandez-Ontiveros DG, Louis MK, Willing AE, Borlongan CV, Sanberg PR (2011) Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res 1398:113–125. https://doi.org/10.1016/j.brainres.2011.04.049

    Article  CAS  PubMed  Google Scholar 

  72. Lin CY, Hsu YH, Lin MH, Yang TH, Chen HM, Chen YC, Hsiao HY, Chen CC et al (2013) Neurovascular abnormalities in humans and mice with Huntington’s disease. Exp Neurol 250:20–30. https://doi.org/10.1016/j.expneurol.2013.08.019

    Article  CAS  PubMed  Google Scholar 

  73. Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagace M, Kuan WL, Saint-Pierre M, Dury RJ, Alata W et al (2015) Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology. Ann Neurol 78(2):160–177. https://doi.org/10.1002/ana.24406

    Article  PubMed  Google Scholar 

  74. Franciosi S, Ryu JK, Shim Y, Hill A, Connolly C, Hayden MR, McLarnon JG, Leavitt BR (2012) Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol Dis 45(1):438–449. https://doi.org/10.1016/j.nbd.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  75. Chen JJ, Salat DH, Rosas HD (2012) Complex relationships between cerebral blood flow and brain atrophy in early Huntington’s disease. Neuroimage 59(2):1043–1051. https://doi.org/10.1016/j.neuroimage.2011.08.112

    Article  PubMed  Google Scholar 

  76. Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F (2006) Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med 47(2):215–222

    CAS  PubMed  Google Scholar 

  77. Andrews TC, Brooks DJ (1998) Advances in the understanding of early Huntington’s disease using the functional imaging techniques of PET and SPET. Mol Med Today 4(12):532–539. https://doi.org/10.1016/s1357-4310(98)01371-9

    Article  CAS  PubMed  Google Scholar 

  78. Padel T, Roth M, Gaceb A, Li JY, Bjorkqvist M, Paul G (2018) Brain pericyte activation occurs early in Huntington’s disease. Exp Neurol 305:139–150. https://doi.org/10.1016/j.expneurol.2018.03.015

    Article  CAS  PubMed  Google Scholar 

  79. Squitieri F, Cannella M, Simonelli M, Sassone J, Martino T, Venditti E, Ciammola A, Colonnese C et al (2009) Distinct brain volume changes correlating with clinical stage, disease progression rate, mutation size, and age at onset prediction as early biomarkers of brain atrophy in Huntington’s disease. CNS Neurosci Ther 15(1):1–11. https://doi.org/10.1111/j.1755-5949.2008.00068.x

    Article  PubMed  PubMed Central  Google Scholar 

  80. Niatsetskaya Z, Basso M, Speer RE, McConoughey SJ, Coppola G, Ma TC, Ratan RR (2010) HIF prolyl hydroxylase inhibitors prevent neuronal death induced by mitochondrial toxins: therapeutic implications for Huntington’s disease and Alzheimer’s disease. Antioxid Redox Signal 12(4):435–443. https://doi.org/10.1089/ars.2009.2800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sarkar S, Raymick J, Mann D, Bowyer JF, Hanig JP, Schmued LC, Paule MG, Chigurupati S (2014) Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinson’s disease. Curr Neurovasc Res 11(1):48–61. https://doi.org/10.2174/1567202610666131124234506

    Article  CAS  PubMed  Google Scholar 

  82. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4(5):399–415. https://doi.org/10.1038/nrn1106nrn1106

    Article  CAS  PubMed  Google Scholar 

  83. Dyrna F, Hanske S, Krueger M, Bechmann I (2013) The blood-brain barrier. J Neuroimmune Pharmacol 8(4):763–773. https://doi.org/10.1007/s11481-013-9473-5

    Article  PubMed  Google Scholar 

  84. Prewitt RL, Rice DC, Dobrian AD (2002) Adaptation of resistance arteries to increases in pressure. Microcirculation 9(4):295–304. https://doi.org/10.1038/sj.mn.7800143

    Article  PubMed  Google Scholar 

  85. Huang L, Nakamura Y, Lo EH, Hayakawa K (2019) Astrocyte signaling in the neurovascular unit after central nervous system injury. Int J Mol Sci 20(2). https://doi.org/10.3390/ijms20020282

  86. Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D (2016) Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat Neurosci 19(12):1619–1627. https://doi.org/10.1038/nn.4428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Faraci FM, Heistad DD (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78(1):53–97. https://doi.org/10.1152/physrev.1998.78.1.53

    Article  CAS  PubMed  Google Scholar 

  88. Golding EM, Marrelli SP, You J, Bryan RM Jr (2002) Endothelium-derived hyperpolarizing factor in the brain: a new regulator of cerebral blood flow? Stroke 33(3):661–663

    Article  PubMed  Google Scholar 

  89. Busse R, Fleming I (2003) Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol Sci 24(1):24–29

    Article  CAS  PubMed  Google Scholar 

  90. Lagaud G, Karicheti V, Knot HJ, Christ GJ, Laher I (2002) Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am J Physiol Heart Circ Physiol 283(6):H2177–H2186. https://doi.org/10.1152/ajpheart.00605.2001283/6/H2177

    Article  CAS  PubMed  Google Scholar 

  91. Kawamura H, Sugiyama T, Wu DM, Kobayashi M, Yamanishi S, Katsumura K, Puro DG (2003) ATP: a vasoactive signal in the pericyte-containing microvasculature of the rat retina. J Physiol 551(Pt 3):787–799. https://doi.org/10.1113/jphysiol.2003.047977jphysiol.2003.047977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sa-Pereira I, Brites D, Brito MA (2012) Neurovascular unit: a focus on pericytes. Mol Neurobiol 45(2):327–347. https://doi.org/10.1007/s12035-012-8244-2

    Article  CAS  PubMed  Google Scholar 

  93. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM et al (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508(7494):55–60. https://doi.org/10.1038/nature13165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gaceb A, Ozen I, Padel T, Barbariga M, Paul G (2018) Pericytes secrete pro-regenerative molecules in response to platelet-derived growth factor-BB. J Cereb Blood Flow Metab 38(1):45–57. https://doi.org/10.1177/0271678X17719645

    Article  CAS  PubMed  Google Scholar 

  95. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153(3):543–553. https://doi.org/10.1083/jcb.153.3.543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5(5):347–360. https://doi.org/10.1038/nrn1387nrn1387

    Article  CAS  PubMed  Google Scholar 

  97. Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26(10):523–530. https://doi.org/10.1016/j.tins.2003.08.008

    Article  CAS  PubMed  Google Scholar 

  98. Peterson EC, Wang Z, Britz G (2011) Regulation of cerebral blood flow. Int J Vasc Med 2011:823525. https://doi.org/10.1155/2011/823525

    Article  PubMed  PubMed Central  Google Scholar 

  99. del Zoppo GJ, Mabuchi T (2003) Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 23(8):879–894. https://doi.org/10.1097/01.WCB.0000078322.96027.78

    Article  PubMed  Google Scholar 

  100. Drake CT, Iadecola C (2007) The role of neuronal signaling in controlling cerebral blood flow. Brain Lang 102(2):141–152. https://doi.org/10.1016/j.bandl.2006.08.002

    Article  PubMed  Google Scholar 

  101. Cauli B, Hamel E (2010) Revisiting the role of neurons in neurovascular coupling. Front Neuroenergetics 2:9. https://doi.org/10.3389/fnene.2010.00009

    Article  PubMed  PubMed Central  Google Scholar 

  102. Kleinfeld D, Blinder P, Drew PJ, Driscoll JD, Muller A, Tsai PS, Shih AY (2011) A guide to delineate the logic of neurovascular signaling in the brain. Front Neuroenergetics 3:1. https://doi.org/10.3389/fnene.2011.00001

    Article  PubMed  PubMed Central  Google Scholar 

  103. Murphy MC, Chan KC, Kim SG, Vazquez AL (2018) Macroscale variation in resting-state neuronal activity and connectivity assessed by simultaneous calcium imaging, hemodynamic imaging and electrophysiology. Neuroimage 169:352–362. https://doi.org/10.1016/j.neuroimage.2017.12.070

    Article  PubMed  Google Scholar 

  104. Zhang X, Pan WJ, Keilholz S (2019) The relationship between local field potentials and the blood-oxygenation-level dependent MRI signal can be non-linear. Front Neurosci 13:1126. https://doi.org/10.3389/fnins.2019.01126

    Article  PubMed  PubMed Central  Google Scholar 

  105. Attwell D, Iadecola C (2002) The neural basis of functional brain imaging signals. Trends Neurosci 25(12):621–625

    Article  CAS  PubMed  Google Scholar 

  106. Khaddaj Mallat R, Mathew John C, Kendrick DJ, Braun AP (2017) The vascular endothelium: a regulator of arterial tone and interface for the immune system. Crit Rev Clin Lab Sci 54(7–8):458–470. https://doi.org/10.1080/10408363.2017.1394267

    Article  CAS  PubMed  Google Scholar 

  107. Andresen J, Shafi NI, Bryan RM Jr (2006) Endothelial influences on cerebrovascular tone. J Appl Physiol (1985) 100(1):318–327. https://doi.org/10.1152/japplphysiol.00937.2005

    Article  CAS  Google Scholar 

  108. Greene C, Campbell M (2016) Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers 4(1):e1138017. https://doi.org/10.1080/21688370.2015.11380171138017

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ando J, Yamamoto K (2013) Flow detection and calcium signalling in vascular endothelial cells. Cardiovasc Res 99(2):260–268. https://doi.org/10.1093/cvr/cvt084cvt084

    Article  CAS  PubMed  Google Scholar 

  110. Galochkina T, Ng Fuk Chong M, Challali L, Abbar S, Etchebest C (2019) New insights into GluT1 mechanics during glucose transfer. Sci Rep 9(1):998. https://doi.org/10.1038/s41598-018-37367-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24(9):1745–1758. https://doi.org/10.1007/s11095-007-9374-5

    Article  CAS  PubMed  Google Scholar 

  112. Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27(11):1766–1791. https://doi.org/10.1038/sj.jcbfm.9600521

    Article  CAS  PubMed  Google Scholar 

  113. Deeken JF, Loscher W (2007) The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13(6):1663–1674. https://doi.org/10.1158/1078-0432.CCR-06-2854

    Article  CAS  PubMed  Google Scholar 

  114. Spector R, Johanson CE (2007) Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E. J Neurochem 103(2):425–438. https://doi.org/10.1111/j.1471-4159.2007.04773.x

    Article  CAS  PubMed  Google Scholar 

  115. Miller DS (2015) Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly. Adv Cancer Res 125:43–70. https://doi.org/10.1016/bs.acr.2014.10.002

    Article  CAS  PubMed  Google Scholar 

  116. Hermann DM, Bassetti CL (2007) Implications of ATP-binding cassette transporters for brain pharmacotherapies. Trends Pharmacol Sci 28(3):128–134. https://doi.org/10.1016/j.tips.2007.01.007

    Article  CAS  PubMed  Google Scholar 

  117. Erdo F, Krajcsi P (2019) Age-related functional and expressional changes in efflux pathways at the blood-brain barrier. Front Aging Neurosci 11:196. https://doi.org/10.3389/fnagi.2019.00196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z et al (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12(3):169–182. https://doi.org/10.1038/nrn2995nrn2995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468(7321):232–243. https://doi.org/10.1038/nature09613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Somlyo AP, Wu X, Walker LA, Somlyo AV (1999) Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134:201–234. https://doi.org/10.1007/3-540-64753-8_5

    Article  CAS  PubMed  Google Scholar 

  121. Greenberg DA, Jin K (2005) From angiogenesis to neuropathology. Nature 438(7070):954–959. https://doi.org/10.1038/nature04481

    Article  CAS  PubMed  Google Scholar 

  122. Segura I, De Smet F, Hohensinner PJ, Ruiz de Almodovar C, Carmeliet P (2009) The neurovascular link in health and disease: an update. Trends Mol Med 15(10):439–451. https://doi.org/10.1016/j.molmed.2009.08.005

    Article  CAS  PubMed  Google Scholar 

  123. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. https://doi.org/10.1146/annurev.neuro.24.1.677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ruan L, Wang B, ZhuGe Q, Jin K (2015) Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res 1623:166–173. https://doi.org/10.1016/j.brainres.2015.02.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Snapyan M, Lemasson M, Brill MS, Blais M, Massouh M, Ninkovic J, Gravel C, Berthod F et al (2009) Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. J Neurosci 29(13):4172–4188. https://doi.org/10.1523/JNEUROSCI.4956-08.200929/13/4172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Karakatsani A, Shah B, Ruiz de Almodovar C (2019) Blood vessels as regulators of neural stem cell properties. Front Mol Neurosci 12:85. https://doi.org/10.3389/fnmol.2019.00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K et al (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304(5675):1338–1340. https://doi.org/10.1126/science.10955051095505

    Article  CAS  PubMed  Google Scholar 

  128. Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T (2018) Bidirectional microglia-neuron communication in health and disease. Front Cell Neurosci 12:323. https://doi.org/10.3389/fncel.2018.00323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Dugas JC, Mandemakers W, Rogers M, Ibrahim A, Daneman R, Barres BA (2008) A novel purification method for CNS projection neurons leads to the identification of brain vascular cells as a source of trophic support for corticospinal motor neurons. J Neurosci 28(33):8294–8305. https://doi.org/10.1523/JNEUROSCI.2010-08.200828/33/8294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang X et al (2008) Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc Natl Acad Sci U S A 105(21):7582–7587. https://doi.org/10.1073/pnas.08011051050801105105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Abbasi M, Gupta V, Chitranshi N, You Y, Dheer Y, Mirzaei M, Graham SL (2018) Regulation of brain-derived neurotrophic factor and growth factor signaling pathways by tyrosine phosphatase Shp2 in the retina: a brief review. Front Cell Neurosci 12:85. https://doi.org/10.3389/fncel.2018.00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Arai K, Lo EH (2009) An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J Neurosci 29(14):4351–4355. https://doi.org/10.1523/JNEUROSCI.0035-09.200929/14/4351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Xing C, Li W, Deng W, Ning M, Lo EH (2018) A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes. J Neuroinflammation 15(1):143. https://doi.org/10.1186/s12974-018-1189-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335(1):75–96. https://doi.org/10.1007/s00441-008-0658-9

    Article  PubMed  Google Scholar 

  135. Hayakawa K, Pham LD, Katusic ZS, Arai K, Lo EH (2012) Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc Natl Acad Sci U S A 109(19):7505–7510. https://doi.org/10.1073/pnas.11211461091121146109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dohgu S, Yamauchi A, Takata F, Naito M, Tsuruo T, Higuchi S, Sawada Y, Kataoka Y (2004) Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells. Cell Mol Neurobiol 24(3):491–497. https://doi.org/10.1023/b:cemn.0000022776.47302.ce

    Article  CAS  PubMed  Google Scholar 

  137. Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M, Maynard T, Gonzalez D et al (2011) The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69(5):893–905. https://doi.org/10.1016/j.neuron.2011.01.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Alto LT, Terman JR (2017) Semaphorins and their signaling mechanisms. Methods Mol Biol 1493:1–25. https://doi.org/10.1007/978-1-4939-6448-2_1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. https://doi.org/10.1038/nature10144nature10144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Majerova P, Michalicova A, Cente M, Hanes J, Vegh J, Kittel A, Kosikova N, Cigankova V et al (2019) Trafficking of immune cells across the blood-brain barrier is modulated by neurofibrillary pathology in tauopathies. PLoS One 14(5):e0217216. https://doi.org/10.1371/journal.pone.0217216PONE-D-18-36131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Pachter JS, de Vries HE, Fabry Z (2003) The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62(6):593–604

    Article  CAS  PubMed  Google Scholar 

  142. Ardura-Fabregat A, Boddeke E, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzeriat K, Dansokho C, Dierkes T et al (2017) Targeting neuroinflammation to treat Alzheimer’s disease. CNS Drugs 31(12):1057–1082. https://doi.org/10.1007/s40263-017-0483-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lampron A, Elali A, Rivest S (2013) Innate immunity in the CNS: redefining the relationship between the CNS and Its environment. Neuron 78(2):214–232. https://doi.org/10.1016/j.neuron.2013.04.005

    Article  CAS  PubMed  Google Scholar 

  144. Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG et al (2011) Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci U S A 108(12):5063–5068. https://doi.org/10.1073/pnas.10154131081015413108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28(1):12–18. https://doi.org/10.1016/j.it.2006.11.004

    Article  CAS  PubMed  Google Scholar 

  146. Mietani K, Sumitani M, Ogata T, Shimojo N, Inoue R, Abe H, Kawamura G, Yamada Y (2019) Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit. PLoS One 14(10):e0222721. https://doi.org/10.1371/journal.pone.0222721PONE-D-19-12923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550. https://doi.org/10.1146/annurev.immunol.021908.132612

    Article  CAS  PubMed  Google Scholar 

  148. Spampinato SF, Merlo S, Fagone E, Fruciano M, Barbagallo C, Kanda T, Sano Y, Purrello M et al (2019) Astrocytes modify migration of PBMCs induced by beta-amyloid in a blood-brain barrier in vitro model. Front Cell Neurosci 13:337. https://doi.org/10.3389/fncel.2019.00337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO (2000) ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 165(6):3375–3383

    Article  CAS  PubMed  Google Scholar 

  150. Cena V, Jativa P (2018) Nanoparticle crossing of blood-brain barrier: a road to new therapeutic approaches to central nervous system diseases. Nanomedicine (Lond) 13(13):1513–1516. https://doi.org/10.2217/nnm-2018-0139

    Article  Google Scholar 

  151. Takeshita Y, Ransohoff RM (2012) Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models. Immunol Rev 248(1):228–239. https://doi.org/10.1111/j.1600-065X.2012.01127.x

    Article  PubMed  PubMed Central  Google Scholar 

  152. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17(7):796–808. https://doi.org/10.1038/nm.2399nm.2399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wesselingh R, Butzkueven H, Buzzard K, Tarlinton D, O'Brien TJ, Monif M (2019) Innate immunity in the central nervous system: a missing piece of the autoimmune encephalitis puzzle? Front Immunol 10:2066. https://doi.org/10.3389/fimmu.2019.02066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T (1998) Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 161(7):3767–3775

    CAS  PubMed  Google Scholar 

  155. Wraith DC, Nicholson LB (2012) The adaptive immune system in diseases of the central nervous system. J Clin Invest 122(4):1172–1179. https://doi.org/10.1172/JCI5864858648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bechmann I, Mor G, Nilsen J, Eliza M, Nitsch R, Naftolin F (1999) FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier. Glia 27(1):62–74. https://doi.org/10.1002/(SICI)1098-1136(199907)27:1<62::AID-GLIA7>3.0.CO;2-S

    Article  CAS  PubMed  Google Scholar 

  157. Yang JX, Pan YY, Wang XX, Qiu YG, Mao W (2018) Endothelial progenitor cells in age-related vascular remodeling. Cell Transplant 27(5):786–795. https://doi.org/10.1177/0963689718779345

    Article  PubMed  PubMed Central  Google Scholar 

  158. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348(7):593–600. https://doi.org/10.1056/NEJMoa022287348/7/593

    Article  PubMed  Google Scholar 

  159. Jessen NA, Munk AS, Lundgaard I, Nedergaard M (2015) The glymphatic system: a beginner’s guide. Neurochem Res 40(12):2583–2599. https://doi.org/10.1007/s11064-015-1581-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Mestre H, Mori Y, Nedergaard M (2020) The brain’s glymphatic system: current controversies. Trends Neurosci. https://doi.org/10.1016/j.tins.2020.04.003

  161. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H et al (2015) Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11(8):457–470. https://doi.org/10.1038/nrneurol.2015.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J (2019) The glymphatic system and waste clearance with brain aging: a review. Gerontology 65(2):106–119. https://doi.org/10.1159/000490349

    Article  PubMed  Google Scholar 

  163. Levit A, Hachinski V, Whitehead SN (2020) Neurovascular unit dysregulation, white matter disease, and executive dysfunction: the shared triad of vascular cognitive impairment and Alzheimer disease. Geroscience. https://doi.org/10.1007/s11357-020-00164-6

  164. Franzblau M, Gonzales-Portillo C, Gonzales-Portillo GS, Diamandis T, Borlongan MC, Tajiri N, Borlongan CV (2013) Vascular damage: a persisting pathology common to Alzheimer’s disease and traumatic brain injury. Med Hypotheses 81(5):842–845. https://doi.org/10.1016/j.mehy.2013.09.012

    Article  CAS  PubMed  Google Scholar 

  165. Kelly P, Denver P, Satchell SC, Ackermann M, Konerding MA, Mitchell CA (2017) Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease. Angiogenesis 20(4):567–580. https://doi.org/10.1007/s10456-017-9568-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Leeuwis AE, Benedictus MR, Kuijer JPA, Binnewijzend MAA, Hooghiemstra AM, Verfaillie SCJ, Koene T, Scheltens P et al (2017) Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer’s disease. Alzheimers Dement 13(5):531–540. https://doi.org/10.1016/j.jalz.2016.08.013

    Article  PubMed  Google Scholar 

  167. Haque ME, Gabr RE, Hasan KM, George S, Arevalo OD, Zha A, Alderman S, Jeevarajan J et al (2019) Ongoing secondary degeneration of the limbic system in patients with ischemic stroke: a longitudinal MRI study. Front Neurol 10:154. https://doi.org/10.3389/fneur.2019.00154

    Article  PubMed  PubMed Central  Google Scholar 

  168. Martin AJ, Friston KJ, Colebatch JG, Frackowiak RS (1991) Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 11(4):684–689. https://doi.org/10.1038/jcbfm.1991.121

    Article  CAS  PubMed  Google Scholar 

  169. Phillips AA, Chan FH, Zheng MM, Krassioukov AV, Ainslie PN (2016) Neurovascular coupling in humans: physiology, methodological advances and clinical implications. J Cereb Blood Flow Metab 36(4):647–664. https://doi.org/10.1177/0271678X156179540271678X15617954

    Article  PubMed  Google Scholar 

  170. Li B, Freeman RD (2010) Neurometabolic coupling in the lateral geniculate nucleus changes with extended age. J Neurophysiol 104(1):414–425. https://doi.org/10.1152/jn.00270.2010jn.00270.2010

    Article  PubMed  PubMed Central  Google Scholar 

  171. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68(3):409–427. https://doi.org/10.1016/j.neuron.2010.09.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR et al (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25(2):270–276. https://doi.org/10.1038/s41591-018-0297-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Hase Y, Horsburgh K, Ihara M, Kalaria RN (2018) White matter degeneration in vascular and other ageing-related dementias. J Neurochem 144(5):617–633. https://doi.org/10.1111/jnc.14271

    Article  CAS  PubMed  Google Scholar 

  174. Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, Barnes SR, Daianu M et al (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24(3):326–337. https://doi.org/10.1038/nm.4482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Shabir O, Berwick J, Francis SE (2018) Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis. BMC Neurosci 19(1):62. https://doi.org/10.1186/s12868-018-0465-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ma Q, Zhao Z, Sagare AP, Wu Y, Wang M, Owens NC, Verghese PB, Herz J et al (2018) Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-beta42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol Neurodegener 13(1):57. https://doi.org/10.1186/s13024-018-0286-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 4:575–590. https://doi.org/10.1016/j.trci.2018.06.014

    Article  Google Scholar 

  178. Zhong G, Lou M (2016) Multimodal imaging findings in normal-appearing white matter of leucoaraiosis: a review. Stroke Vasc Neurol 1(2):59–63. https://doi.org/10.1136/svn-2016-000021svn-2016-000021

    Article  PubMed  PubMed Central  Google Scholar 

  179. Topakian R, Barrick TR, Howe FA, Markus HS (2010) Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry 81(2):192–197. https://doi.org/10.1136/jnnp.2009.172072jnnp.2009.172072

    Article  CAS  PubMed  Google Scholar 

  180. Balusu S, Brkic M, Libert C, Vandenbroucke RE (2016) The choroid plexus-cerebrospinal fluid interface in Alzheimer’s disease: more than just a barrier. Neural Regen Res 11(4):534–537. https://doi.org/10.4103/1673-5374.180372NRR-11-534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chen RL, Kassem NA, Redzic ZB, Chen CP, Segal MB, Preston JE (2009) Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol 44(4):289–296. https://doi.org/10.1016/j.exger.2008.12.004

    Article  CAS  PubMed  Google Scholar 

  182. Boese AC, Hamblin MH, Lee JP (2019) Neural stem cell therapy for neurovascular injury in Alzheimer’s disease. Exp Neurol. https://doi.org/10.1016/j.expneurol.2019.113112

  183. Erdo F, Denes L, de Lange E (2017) Age-associated physiological and pathological changes at the blood-brain barrier: a review. J Cereb Blood Flow Metab 37(1):4–24. https://doi.org/10.1177/0271678X16679420

    Article  CAS  PubMed  Google Scholar 

  184. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120(4):545–555. https://doi.org/10.1016/j.cell.2005.02.008

    Article  CAS  PubMed  Google Scholar 

  185. Walsh DM, Townsend M, Podlisny MB, Shankar GM, Fadeeva JV, El Agnaf O, Hartley DM, Selkoe DJ (2005) Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation. J Neurosci 25(10):2455–2462. https://doi.org/10.1523/JNEUROSCI.4391-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Gotz J, Bodea LG, Goedert M (2018) Rodent models for Alzheimer disease. Nat Rev Neurosci 19(10):583–598. https://doi.org/10.1038/s41583-018-0054-8

    Article  CAS  PubMed  Google Scholar 

  187. Ghilardi JR, Catton M, Stimson ER, Rogers S, Walker LC, Maggio JE, Mantyh PW (1996) Intra-arterial infusion of [125I]A beta 1-40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport 7(15–17):2607–2611

    Article  CAS  PubMed  Google Scholar 

  188. Martel CL, Mackic JB, McComb JG, Ghiso J, Zlokovic BV (1996) Blood-brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer’s amyloid beta in guinea pigs. Neurosci Lett 206(2–3):157–160

    Article  CAS  PubMed  Google Scholar 

  189. Van Gool B, Storck SE, Reekmans SM, Lechat B, Gordts P, Pradier L, Pietrzik CU, Roebroek AJM (2019) LRP1 Has a predominant role in production over clearance of abeta in a mouse model of Alzheimer’s disease. Mol Neurobiol 56(10):7234–7245. https://doi.org/10.1007/s12035-019-1594-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ et al (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 13(9):1029–1031. https://doi.org/10.1038/nm1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295(5563):2264–2267. https://doi.org/10.1126/science.1067568295/5563/2264

    Article  CAS  PubMed  Google Scholar 

  192. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159(2):439–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zha Q, Ruan Y, Hartmann T, Beyreuther K, Zhang D (2004) GM1 ganglioside regulates the proteolysis of amyloid precursor protein. Mol Psychiatry 9(10):946–952. https://doi.org/10.1038/sj.mp.4001509

    Article  CAS  PubMed  Google Scholar 

  194. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J et al (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 106(16):6820–6825. https://doi.org/10.1073/pnas.09003451060900345106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Matsuoka Y, Saito M, LaFrancois J, Gaynor K, Olm V, Wang L, Casey E, Lu Y et al (2003) Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23(1):29–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Bongarzone S, Savickas V, Luzi F, Gee AD (2017) Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J Med Chem 60(17):7213–7232. https://doi.org/10.1021/acs.jmedchem.7b00058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L et al (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7):907–913. https://doi.org/10.1038/nm890nm890

    Article  CAS  PubMed  Google Scholar 

  198. Mackic JB, Stins M, McComb JG, Calero M, Ghiso J, Kim KS, Yan SD, Stern D et al (1998) 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(4):734–743. https://doi.org/10.1172/JCI2029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Giri R, Shen Y, Stins M, Du Yan S, Schmidt AM, Stern D, Kim KS, Zlokovic B et al (2000) beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol 279(6):C1772–C1781. https://doi.org/10.1152/ajpcell.2000.279.6.C1772

    Article  CAS  PubMed  Google Scholar 

  200. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L et al (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382(6593):685–691. https://doi.org/10.1038/382685a0

    Article  CAS  PubMed  Google Scholar 

  201. Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA (2010) Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid beta-peptide elimination from the brain. J Neurochem 115(5):1077–1089. https://doi.org/10.1111/j.1471-4159.2010.07002.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hou H, Habib A, Zi D, Tian K, Tian J, Giunta B, Sawmiller D, Tan J (2017) Low-density lipoprotein receptor-related protein-1 (LRP1) C4408R mutant promotes amyloid precursor protein (APP) alpha-cleavage in vitro. Neuromolecular Med 19(2–3):300–308. https://doi.org/10.1007/s12017-017-8446-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE (2004) Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem 279(19):20296–20306. https://doi.org/10.1074/jbc.M312946200M312946200

    Article  CAS  PubMed  Google Scholar 

  204. Hecht M, Kramer LM, von Arnim CAF, Otto M, Thal DR (2018) Capillary cerebral amyloid angiopathy in Alzheimer’s disease: association with allocortical/hippocampal microinfarcts and cognitive decline. Acta Neuropathol 135(5):681–694. https://doi.org/10.1007/s00401-018-1834-y

    Article  CAS  PubMed  Google Scholar 

  205. Thal DR, Griffin WS, de Vos RA, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115(6):599–609. https://doi.org/10.1007/s00401-008-0366-2

    Article  CAS  PubMed  Google Scholar 

  206. Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA et al (2000) Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci U S A 97(17):9735–9740. https://doi.org/10.1073/pnas.97.17.9735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Tachibana M, Holm ML, Liu CC, Shinohara M, Aikawa T, Oue H, Yamazaki Y, Martens YA et al (2019) APOE4-mediated amyloid-beta pathology depends on its neuronal receptor LRP1. J Clin Invest 129(3):1272–1277. https://doi.org/10.1172/JCI124853124853

    Article  PubMed  PubMed Central  Google Scholar 

  208. Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118(12):4002–4013. https://doi.org/10.1172/JCI3666336663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. DeMattos RB, Cirrito JR, Parsadanian M, May PC, O'Dell MA, Taylor JW, Harmony JA, Aronow BJ et al (2004) ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41(2):193–202

    Article  CAS  PubMed  Google Scholar 

  210. Storck SE, Hartz AMS, Bernard J, Wolf A, Kachlmeier A, Mahringer A, Weggen S, Pahnke J et al (2018) The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain Behav Immun 73:21–33. https://doi.org/10.1016/j.bbi.2018.07.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Owen JB, Sultana R, Aluise CD, Erickson MA, Price TO, Bu G, Banks WA, Butterfield DA (2010) Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Abeta accumulation in AD brain. Free Radic Biol Med 49(11):1798–1803. https://doi.org/10.1016/j.freeradbiomed.2010.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Behl M, Zhang Y, Shi Y, Cheng J, Du Y, Zheng W (2010) Lead-induced accumulation of beta-amyloid in the choroid plexus: role of low density lipoprotein receptor protein-1 and protein kinase C. Neurotoxicology 31(5):524–532. https://doi.org/10.1016/j.neuro.2010.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Kanemitsu H, Tomiyama T, Mori H (2003) Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett 350(2):113–116

    Article  CAS  PubMed  Google Scholar 

  214. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E et al (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292(5521):1550–1552. https://doi.org/10.1126/science.1059946292/5521/1550

    Article  CAS  PubMed  Google Scholar 

  215. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A et al (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 273(49):32730–32738

    Article  CAS  PubMed  Google Scholar 

  216. Melchor JP, Pawlak R, Strickland S (2003) The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J Neurosci 23(26):8867–8871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H et al (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26(43):10939–10948. https://doi.org/10.1523/JNEUROSCI.2085-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Smith AJ, Duan T, Verkman AS (2019) Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer’s disease by remodeling peri-plaque astrocyte structure. Acta Neuropathol Commun 7(1):74. https://doi.org/10.1186/s40478-019-0728-0

    Article  PubMed  PubMed Central  Google Scholar 

  219. Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T et al (2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. Mol Neurodegener 10:58. https://doi.org/10.1186/s13024-015-0056-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Bianca VD, Dusi S, Bianchini E, Dal Pra I, Rossi F (1999) beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer’s disease. J Biol Chem 274(22):15493–15499

    Article  CAS  PubMed  Google Scholar 

  221. Galvan V, Hart MJ (2016) Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer’s disease. Biochim Biophys Acta 1862(5):992–1007. https://doi.org/10.1016/j.bbadis.2015.11.010

    Article  CAS  PubMed  Google Scholar 

  222. Miano JM (2003) Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol 35(6):577–593

    Article  CAS  PubMed  Google Scholar 

  223. Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, Krieg PA, Olson EN (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105(7):851–862

    Article  CAS  PubMed  Google Scholar 

  224. Gejl M, Brock B, Egefjord L, Vang K, Rungby J, Gjedde A (2017) Blood-brain glucose transfer in Alzheimer’s disease: effect of GLP-1 analog treatment. Sci Rep 7(1):17490. https://doi.org/10.1038/s41598-017-17718-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Marcus C, Mena E, Subramaniam RM (2014) Brain PET in the diagnosis of Alzheimer’s disease. Clin Nucl Med 39(10):e413–e422; quiz e423–416. https://doi.org/10.1097/RLU.000000000000054700003072-201410000-00026

    Article  PubMed  PubMed Central  Google Scholar 

  226. Small GW, Kuhl DE, Riege WH, Fujikawa DG, Ashford JW, Metter EJ, Mazziotta JC (1989) Cerebral glucose metabolic patterns in Alzheimer’s disease. Effect of gender and age at dementia onset. Arch Gen Psychiatry 46(6):527–532

    Article  CAS  PubMed  Google Scholar 

  227. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A (2003) Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 30(8):1104–1113. https://doi.org/10.1007/s00259-003-1194-1

    Article  PubMed  Google Scholar 

  228. Herholz K (2003) PET studies in dementia. Ann Nucl Med 17(2):79–89

    Article  PubMed  Google Scholar 

  229. Chen WP, Matsunari I, Noda A, Yanase D, Yajima K, Takeda N, Yamada M, Minoshima S et al (2005) Rapid scanning protocol for brain (18)F-FDG PET: a validation study. J Nucl Med 46(10):1633–1641

    PubMed  Google Scholar 

  230. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380(6570):168–171. https://doi.org/10.1038/380168a0

    Article  CAS  PubMed  Google Scholar 

  231. Amtul Z, Yang J, Lee TY, Cechetto DF (2019) Pathological changes in microvascular morphology, density, size and responses following comorbid cerebral injury. Front Aging Neurosci 11:47. https://doi.org/10.3389/fnagi.2019.00047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70(5):2212–2215

    Article  CAS  PubMed  Google Scholar 

  233. Hamilos M, Petousis S, Parthenakis F (2018) Interaction between platelets and endothelium: from pathophysiology to new therapeutic options. Cardiovasc Diagn Ther 8(5):568–580. https://doi.org/10.21037/cdt.2018.07.01cdt-08-05-568

    Article  PubMed  PubMed Central  Google Scholar 

  234. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC et al (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160(1):101–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Marchesi VT (2011) Alzheimer’s dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J 25(1):5–13. https://doi.org/10.1096/fj.11-0102ufm25/1/5

    Article  CAS  PubMed  Google Scholar 

  236. Edwards Iii GA, Gamez N, Escobedo G Jr, Calderon O, Moreno-Gonzalez I (2019) Modifiable risk factors for Alzheimer’s disease. Front Aging Neurosci 11:146. https://doi.org/10.3389/fnagi.2019.00146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. de la Torre JC (2010) Vascular risk factor detection and control may prevent Alzheimer’s disease. Ageing Res Rev 9(3):218–225. https://doi.org/10.1016/j.arr.2010.04.002

    Article  CAS  PubMed  Google Scholar 

  238. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R (2007) Relation of diabetes to mild cognitive impairment. Arch Neurol 64(4):570–575. https://doi.org/10.1001/archneur.64.4.570

    Article  PubMed  Google Scholar 

  239. Iadecola C, Davisson RL (2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7(6):476–484. https://doi.org/10.1016/j.cmet.2008.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K (2008) Central obesity and increased risk of dementia more than three decades later. Neurology 71(14):1057–1064. https://doi.org/10.1212/01.wnl.0000306313.89165.ef01.wnl.0000306313.89165.ef

    Article  CAS  PubMed  Google Scholar 

  241. DeMaagd G, Philip A (2015) Parkinson’s disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P T 40(8):504–532

    PubMed  PubMed Central  Google Scholar 

  242. Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285(19):3657–3668. https://doi.org/10.1111/febs.14607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Pilotto A, Turrone R, Liepelt-Scarfone I, Bianchi M, Poli L, Borroni B, Alberici A, Premi E et al (2016) Vascular risk factors and cognition in Parkinson’s disease. J Alzheimers Dis 51(2):563–570. https://doi.org/10.3233/JAD-150610

    Article  CAS  PubMed  Google Scholar 

  244. Gutteridge DS, Saredakis D, Badcock NA, Collins-Praino LE, Keage HAD (2020) Cerebrovascular function during cognition in Parkinson’s disease: a functional transcranial Doppler sonography study. J Neurol Sci 408:116578. https://doi.org/10.1016/j.jns.2019.116578

    Article  PubMed  Google Scholar 

  245. Gray MT, Woulfe JM (2015) Striatal blood-brain barrier permeability in Parkinson’s disease. J Cereb Blood Flow Metab 35(5):747–750. https://doi.org/10.1038/jcbfm.2015.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA (2003) Head trauma preceding PD: a case-control study. Neurology 60(10):1610–1615. https://doi.org/10.1212/01.wnl.0000068008.78394.2c

    Article  CAS  PubMed  Google Scholar 

  247. Foltynie T, Barker R, Brayne C (2002) Vascular parkinsonism: a review of the precision and frequency of the diagnosis. Neuroepidemiology 21(1):1–7. https://doi.org/10.1159/000048607

    Article  PubMed  Google Scholar 

  248. Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R (2017) Dopamine and levodopa prodrugs for the treatment of Parkinson’s disease. Molecules 23(1). https://doi.org/10.3390/molecules23010040

  249. Winblad B, Kilander L, Eriksson S, Minthon L, Batsman S, Wetterholm AL, Jansson-Blixt C, Haglund A (2006) Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 367(9516):1057–1065. https://doi.org/10.1016/S0140-6736(06)68350-5

    Article  CAS  PubMed  Google Scholar 

  250. Ahmed SS, Husain RS, Kumar S, Ramakrishnan V (2016) Association between MDR1 gene polymorphisms and Parkinson’s disease in Asian and Caucasian populations: a meta-analysis. J Neurol Sci 368:255–262. https://doi.org/10.1016/j.jns.2016.07.041

    Article  CAS  PubMed  Google Scholar 

  251. Carro E, Trejo JL, Gerber A, Loetscher H, Torrado J, Metzger F, Torres-Aleman I (2006) Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol Aging 27(9):1250–1257. https://doi.org/10.1016/j.neurobiolaging.2005.06.015

    Article  CAS  PubMed  Google Scholar 

  252. Spuch C, Antequera D, Portero A, Orive G, Hernandez RM, Molina JA, Bermejo-Pareja F, Pedraz JL et al (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(21):5608–5618. https://doi.org/10.1016/j.biomaterials.2010.03.042

    Article  CAS  PubMed  Google Scholar 

  253. Chao YX, He BP, Tay SS (2009) Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson’s disease. J Neuroimmunol 216(1–2):39–50. https://doi.org/10.1016/j.jneuroim.2009.09.003

    Article  CAS  PubMed  Google Scholar 

  254. Manrique-Castano D, Sardari M, Silva de Carvalho T, Doeppner TR, Popa-Wagner A, Kleinschnitz C, Chan A, Hermann DM (2019) Deactivation of ATP-binding cassette transporters ABCB1 and ABCC1 does not influence post-ischemic neurological deficits, secondary neurodegeneration and neurogenesis, but induces subtle microglial morphological changes. Front Cell Neurosci 13:412. https://doi.org/10.3389/fncel.2019.00412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Bartels AL, Kortekaas R, Bart J, Willemsen AT, de Klerk OL, de Vries JJ, van Oostrom JC, Leenders KL (2009) Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol Aging 30(11):1818–1824. https://doi.org/10.1016/j.neurobiolaging.2008.02.002

    Article  CAS  PubMed  Google Scholar 

  256. Sun H, Liang R, Yang B, Zhou Y, Liu M, Fang F, Ding J, Fan Y et al (2016) Aquaporin-4 mediates communication between astrocyte and microglia: implications of neuroinflammation in experimental Parkinson’s disease. Neuroscience 317:65–75. https://doi.org/10.1016/j.neuroscience.2016.01.003

    Article  CAS  PubMed  Google Scholar 

  257. Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V, Gao J, Pandey A et al (2019) Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci U S A 116(10):4696–4705. https://doi.org/10.1073/pnas.1818415116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ (2013) Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol 125(6):777–794. https://doi.org/10.1007/s00401-013-1125-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Snowden JS (2017) The neuropsychology of Huntington’s disease. Arch Clin Neuropsychol 32(7):876–887. https://doi.org/10.1093/arclin/acx086

    Article  PubMed  Google Scholar 

  260. McColgan P, Tabrizi SJ (2018) Huntington’s disease: a clinical review. Eur J Neurol 25(1):24–34. https://doi.org/10.1111/ene.13413

    Article  CAS  PubMed  Google Scholar 

  261. Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10(1):83–98. https://doi.org/10.1016/S1474-4422(10)70245-3

    Article  CAS  PubMed  Google Scholar 

  262. Ghosh R, Tabrizi SJ (2018) Clinical features of Huntington’s disease. Adv Exp Med Biol 1049:1–28. https://doi.org/10.1007/978-3-319-71779-1_1

    Article  CAS  PubMed  Google Scholar 

  263. Hsiao HY, Chen YC, Huang CH, Chen CC, Hsu YH, Chen HM, Chiu FL, Kuo HC et al (2015) Aberrant astrocytes impair vascular reactivity in Huntington disease. Ann Neurol 78(2):178–192. https://doi.org/10.1002/ana.24428

    Article  CAS  PubMed  Google Scholar 

  264. Sagare AP, Bell RD, Srivastava A, Sengillo JD, Singh I, Nishida Y, Chow N, Zlokovic BV (2013) A lipoprotein receptor cluster IV mutant preferentially binds amyloid-beta and regulates its clearance from the mouse brain. J Biol Chem 288(21):15154–15166. https://doi.org/10.1074/jbc.M112.439570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Jaeger LB, Dohgu S, Hwang MC, Farr SA, Murphy MP, Fleegal-DeMotta MA, Lynch JL, Robinson SM et al (2009) Testing the neurovascular hypothesis of Alzheimer’s disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition. J Alzheimers Dis 17(3):553–570. https://doi.org/10.3233/JAD-2009-1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Gschanes A, Boado R, Sametz W, Windisch M (2000) The drug cerebrolysin and its peptide fraction E021 increase the abundance of the blood-brain barrier GLUT1 glucose transporter in brains of young and old rats. Histochem J 32(2):71–77. https://doi.org/10.1023/a:1004003008683

    Article  CAS  PubMed  Google Scholar 

  267. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S et al (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122(4):1377–1392. https://doi.org/10.1172/JCI58642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Religa P, Cao R, Religa D, Xue Y, Bogdanovic N, Westaway D, Marti HH, Winblad B et al (2013) VEGF significantly restores impaired memory behavior in Alzheimer’s mice by improvement of vascular survival. Sci Rep 3:2053. https://doi.org/10.1038/srep02053

    Article  PubMed  PubMed Central  Google Scholar 

  269. Girolamo F, Errede M, Longo G, Annese T, Alias C, Ferrara G, Morando S, Trojano M et al (2019) Defining the role of NG2-expressing cells in experimental models of multiple sclerosis. A biofunctional analysis of the neurovascular unit in wild type and NG2 null mice. PLoS One 14(3):e0213508. https://doi.org/10.1371/journal.pone.0213508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J et al (2010) Pericytes regulate the blood-brain barrier. Nature 468(7323):557–561. https://doi.org/10.1038/nature09522

    Article  CAS  PubMed  Google Scholar 

  271. Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT (2015) Resveratrol decreases the insoluble Abeta1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience 310:641–649. https://doi.org/10.1016/j.neuroscience.2015.10.006

    Article  CAS  PubMed  Google Scholar 

  272. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280(45):37377–37382. https://doi.org/10.1074/jbc.M508246200

    Article  CAS  PubMed  Google Scholar 

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Funding

Our work is supported by William and Ella Owens Medical Research Foundation, the Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center and Deanship of Scientific Research at King Saud University (RG-1441-355).

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Authors and Affiliations

  1. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Ajmal Ahmad

  2. Department of Neurology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, Suite 432 Link Building, Memphis, TN, 38163, USA

    Vanisha Patel, Jianfeng Xiao & Mohammad Moshahid Khan

  3. Division of Rehabilitation Sciences and Department of Physical therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, USA

    Mohammad Moshahid Khan

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  1. Ajmal Ahmad
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  2. Vanisha Patel
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  3. Jianfeng Xiao
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  4. Mohammad Moshahid Khan
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Correspondence to Mohammad Moshahid Khan.

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Ahmad, A., Patel, V., Xiao, J. et al. The Role of Neurovascular System in Neurodegenerative Diseases. Mol Neurobiol 57, 4373–4393 (2020). https://doi.org/10.1007/s12035-020-02023-z

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