Molecular Neurobiology

, Volume 34, Issue 3, pp 181–192 | Cite as

Natural secretory products of human neural and microvessel endothelial cells

Implications in pathogenic “Spreading” and Alzheimer's disease
  • Yuhai Zhao
  • Jian-Guo Cui
  • Walter J. Lukiw


Neurons, glia, and endothelial cells of the cerebral microvasculature co-exist in intimate proximity in nervous tissues, and their homeostatic interactions in health, as well as coordinated response to injury, have led to the concept that they form the basic elements of a functional neurovascular unit. During the course of normal cellular metabolism, growth, and development, each of these brain cell types secrete various species of potentially neurotoxic peptides and factors, events that increase in magnitude as brain cells age. This article reviews contemporary research on the secretory products of the three primary cell types that constitute the neurovascular unit in deep brain regions. We provide some novel in vitro data that illustrate potentially pathogenic paracrine effects within primary cells of the neurovascular unit. For example, the pro-inflammatory cytokine interleukin (IL)-1β was found to stimulate amyloid-β (Aβ) peptide release from human neural cells, and human brain microvessel endothelial cells exposed to transient hypoxia were found to secrete IL-1β at concentrations known to induce Aβ42 peptide release from human neural cells. Hypoxia and excessive IL-1β and Aβ42 abundance are typical pathogenic stress factors implicated in the initiation and development of common, chronic neurological disorders such as Alzheimer's disease. These data support the hypothesis that paracrine effects of stressed constituent cells of the neurovascular unit may contribute to “spreading effects” characteristic of progressive neurodegenerative disorders.

Index Entries

Alzheimer's disease amyloid-β 42 human neural cells IL-1β, microvessel endothelial cells neurodegeneration neurovascular unit paracrine effects primary culture spreading effects 


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  1. 1.
    Iadecola C. (2004) Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360.PubMedCrossRefGoogle Scholar
  2. 2.
    Girouard H. and Iadecola C. (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol. 100, 328–335.PubMedCrossRefGoogle Scholar
  3. 3.
    McCarty J. H. (2005) Cell biology of the neurovascular unit: implications for drug delivery across the blood-brain barrier. Assay Drug Dev. Technol. 3, 89–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Hawkins B. T. and Davis T. P. (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185.PubMedCrossRefGoogle Scholar
  5. 5.
    Nicoll J. A., Yamada M., Frackowiak J., Mazur-Kolecka, B., and Weller R. O. (2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer's disease. Pro-CAA position statement. Neurobiol. Aging 25, 589–597.PubMedCrossRefGoogle Scholar
  6. 6.
    Bailey T. L., Rivara C. B., Rocher A. B., and Hof P. R. (2004) The nature and effects of cortical microvascular pathology in aging and Alz. heimer's disease. Neurol. Res. 26, 573–578.PubMedCrossRefGoogle Scholar
  7. 7.
    Humpel C. and Marksteiner J. (2005) Cerebrovascular damage as a cause for Alzheimer's disease. Curr Neurovasc Res 2, 341–347.PubMedCrossRefGoogle Scholar
  8. 8.
    Carmeliet P. (2003) Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4, 710–720.PubMedCrossRefGoogle Scholar
  9. 9.
    Zlokovic B. V. (2005) Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208.PubMedCrossRefGoogle Scholar
  10. 10.
    Garcia-Segura L. M. and McCarthy M. M. (2004) Role of glia in neuroendocrine function. Endocrinology 145, 1082–1086.PubMedCrossRefGoogle Scholar
  11. 11.
    Benarroch E. E. (2005) Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin. Proc. 80, 1326–1338.PubMedGoogle Scholar
  12. 13.
    Ward N. L. and Lamanna J. C. (2004) The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol. Res. 26, 870–883.PubMedCrossRefGoogle Scholar
  13. 13.
    Lukiw W. J., Cui J. G., Marcheselli V. L., et al. (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783.PubMedCrossRefGoogle Scholar
  14. 14.
    Hardy J. A. and Higgins G. A. (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184, 185.PubMedCrossRefGoogle Scholar
  15. 15.
    Selkoe D. J. (1994) Alzheimer's disease: a central role for amyloid. J. Neuropathol. Exp. Neurol. 53, 438–447.PubMedGoogle Scholar
  16. 16.
    Kawarabayashi T., Younkin L. H., Saido T. C., Shoji M., Ashe K. H., and Younkin S. G. (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 372–381.PubMedGoogle Scholar
  17. 17.
    Lee E. B., Skovronsky D. M., Abtahian F., Doms R. W., and Lee V. M. (2003) Secretion and intracellular generation of truncated Abeta in betasite amyloid-beta precursor protein-cleaving enzyme expressing human neurons. J. Biol. Chem. 278, 4458–4466.PubMedCrossRefGoogle Scholar
  18. 18.
    Yao Y., Chinnici C., Tang H., Trojanowski J. Q., Lee V. M., and Pratico D. (2004) Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis. J Neuroinflammation 1, 21.PubMedCrossRefGoogle Scholar
  19. 19.
    Mattson M. P. (2004) Pathways towards and away from Alzheimer's disease. Nature 430, 631–639.PubMedCrossRefGoogle Scholar
  20. 20.
    Gandy S. (2005) The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J. Clin. Invest. 115, 1121–1129.PubMedCrossRefGoogle Scholar
  21. 21.
    Turner P. R., O'Connor K., Tate W. P., and Abraham W. C. (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog. Neurobiol. 70, 1–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Holscher C. (2005) Development of beta-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies. Rev. Neurosci. 16, 181–212.PubMedGoogle Scholar
  23. 23.
    Kim W. and Hecht M. H. (2005) Sequence determinants of enhanced amyloidogenicity of Alzheimer Aβ42 peptide relative to Aβ40. J. Biol. Chem. 280, 35,069–35,076.Google Scholar
  24. 24.
    Bitan G., Kirkitadze M. D., Lomakin A., Vollers S. S., Benedek G. B., and Teplow D. B. (2003) Amyloid beta-protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. USA 100, 330–335.PubMedCrossRefGoogle Scholar
  25. 25.
    Herzig M. C., Winkler D. T., Burgermeister P., et al. (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat. Neurosci. 7, 954–960.PubMedCrossRefGoogle Scholar
  26. 26.
    Klein W. L., Krafft G. A., and Finch C. E. (2001) Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224.PubMedCrossRefGoogle Scholar
  27. 27.
    Lambert M. P., Barlow A. K., Chromy B. A., et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453.PubMedCrossRefGoogle Scholar
  28. 28.
    Nilsberth C., Westlind-Danielsson A., Eckman C. B., et al. (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat. Neurosci. 4, 887–893.PubMedCrossRefGoogle Scholar
  29. 29.
    Hardy J. and Selkoe D. J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356.PubMedCrossRefGoogle Scholar
  30. 30.
    Canevari L., Abramov A. Y., and Duchen M. R. (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem. Res. 29, 637–650.PubMedCrossRefGoogle Scholar
  31. 31.
    Bondy S. C., Guo-Ross S. X., and Truong A. T. (1998) Promotion of transition metal-induced reactive oxygen species formation by beta-amyloid. Brain Res. 799, 91–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Lynch T., Cherny R. A., and Bush A. I. (2000) Oxidative processes in Alzheimer's disease: the role of abeta-metal interactions. Exp. Gerontol. 35, 445–451.PubMedCrossRefGoogle Scholar
  33. 33.
    Alexandrov P. N., Zhao Y., Pogue A. I., et al. (2005) Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells. J. Alzheimers Dis. 8, 117–127.PubMedGoogle Scholar
  34. 34.
    Caspersen C., Wang N., Yao J., et al. (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 19, 2040, 2041.PubMedGoogle Scholar
  35. 35.
    Rodrigues C. M., Sola S., Brito M. A., Brondino C. D., Brites D., and Moura J. J. (2001) Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem. Biophys. Res. Commun. 281, 468–474.PubMedCrossRefGoogle Scholar
  36. 36.
    Morais Cardoso S., Swerdlow R. H., and Oliveira C. R. (2002) Induction of cytochrome c-mediated apoptosis by amyloid beta 25–35 requires functional mitochondria. Brain Res. 931, 117–125.PubMedCrossRefGoogle Scholar
  37. 37.
    Nedergaard M., Ransom B., and Goldman S. A. (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 26, 523–530.PubMedCrossRefGoogle Scholar
  38. 38.
    Blasko I., Stampfer-Kountchev M., Robatscher P., Veerhuis R., Eikelenboom P., and Grubeck-Loebenstein B. (2004) How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging Cell 3, 169–176.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagele R. G., Wegiel J., Venkataraman V., Imaki H., Wang K. C., and Wegiel J. (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol. Aging 25, 663–674.PubMedCrossRefGoogle Scholar
  40. 40.
    Johnstone M., Gearing A. J., and Miller K. M. (1999) A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J. Neuroimmunol. 93, 182–193.PubMedCrossRefGoogle Scholar
  41. 41.
    Koehler R. C., Gebremedhin D., and Harder D. R. (2006) Role of astrocytes in cerebrovascular regulation. J. Appl. Physiol. 100, 307–317.PubMedCrossRefGoogle Scholar
  42. 42.
    Zonta M., Angulo M. C., Gobbo S., et al. (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Cui J. G., Kuroda H., Chandrasekharan N. V., et al. (2004) Cyclooxygenase-3 gene expression in Alzheimer hippocampus and in stressed human neural cells. Neurochem. Res. 29, 1731–1737.PubMedCrossRefGoogle Scholar
  44. 44.
    Pellerin L. (2005) How astrocytes feed hungry neurons. Mol. Neurobiol. 32, 59–72.PubMedCrossRefGoogle Scholar
  45. 45.
    Benzing W. C., Wujek J. R., Ward E. K., et al. (1999) Evidence for glial-mediated inflammation in aged APP (SW) transgenic mice. Neurobiol. Aging 20, 581–589.PubMedCrossRefGoogle Scholar
  46. 46.
    Blasko I., Marx F., Steiner E., Hartmann T., and Grubeck-Loebenstein B. (1999) TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J. 13, 63–68.PubMedGoogle Scholar
  47. 47.
    Blasko I., Veerhuis R., Stampfer-Kountchev M., Saurwein-Teissl M., Eikelenboom P., and Grubeck-Loebenstein B. (2000) Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1–40 and Abeta1–42 by human astrocytes. Neurobiol. Dis. 7, 682–689.PubMedCrossRefGoogle Scholar
  48. 48.
    McGeer P. L. and McGeer E. G. (2002) Local neuroinflammation and the progression of Alzheimer's disease. J. Neurovirol 8, 529–538.PubMedCrossRefGoogle Scholar
  49. 49.
    Lindberg C., Selenica M. L., Westlind-Danielsson A., and Schultzberg M. (2005) Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. J. Mol. Neurosci. 27, 1–12.PubMedCrossRefGoogle Scholar
  50. 50.
    Rogers J., Strohmeyer R., Kovelowski C. J., and Li R. (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40, 260–269.PubMedCrossRefGoogle Scholar
  51. 51.
    Bard F., Cannon C., Barbour R., et al. (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919.PubMedCrossRefGoogle Scholar
  52. 52.
    Jantzen P. T., Connor K. E., DiCarlo G., et al. (2002) Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci. 22, 2246–2254.PubMedGoogle Scholar
  53. 53.
    Shen Q., Goderie S. K., Jin L., et al. (2004) Endothelial cells stimulate self-renewal and exp and neurogenesis of neural stem cells. Science 304, 1338–1340.PubMedCrossRefGoogle Scholar
  54. 54.
    Louissaint A., Jr., Rao S., Leventhal C., and Goldman S. A. (2002) Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960.PubMedCrossRefGoogle Scholar
  55. 55.
    Honma Y., Araki T., Gianino S. et al. (2002) Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35, 267–282.PubMedCrossRefGoogle Scholar
  56. 56.
    Koistinaho M. and Koistinaho J. (2005) Interactions between Alzheimer's disease and cerebral ischemia—focus on inflammation. Brain Res. Brain Res. Rev. 48, 240–250.PubMedCrossRefGoogle Scholar
  57. 57.
    Zlokovic B. V., Deane R., Sallstrom J., Chow N., and Miano J. M. (2005) Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol. 15, 78–83.PubMedCrossRefGoogle Scholar
  58. 58.
    Tanzi R. E., Moir R. D., and Wagner S. L. (2004) Clearance of Alzheimer's Abeta peptide: the many roads to perdition. Neuron 43, 605–608.PubMedGoogle Scholar
  59. 59.
    Lukiw W. J., Pappolla M., Pelaez R. P., and Bazan N. G. (2005) Alzheimer's disease—a dysfunction in cholesterol and lipid metabolism. Cell. Mol. Neurobiol. 25, 475–483.PubMedCrossRefGoogle Scholar
  60. 60.
    Alexandroy P., Cui J. G., Zhao Y., and Lukiw W. J. (2005) 24S-hydroxycholesterol induces inflammatory gene expression in primary human neural cells. Neuroreport 16, 909–913.CrossRefGoogle Scholar
  61. 61.
    de la Torre J. C. (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33, 1152–1162.PubMedCrossRefGoogle Scholar
  62. 62.
    Grammas P. and Ovase R. (2001) Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol. Aging 22, 837–842.PubMedCrossRefGoogle Scholar
  63. 63.
    Grammas P., Ottman T., Reimann-Philipp U., Larabee J., and Weigel P. H. (2004) Injured brain endothelial cells release neurotoxic thrombin. J. Alzheimers Dis. 6, 275–281.PubMedGoogle Scholar
  64. 64.
    Christov A., Ottman J. T., and Grammas P. (2004) Vascular inflammatory, oxidative and protease-based processes: implications for neuronal cell death in Alzheimer's disease. Neurol. Res. 26, 540–546.PubMedCrossRefGoogle Scholar
  65. 65.
    Bazan N. G., and Lukiw W. J. (2002) Cyclooxygenase-2 and presenilin-1 gene expression induced by interleukin-1beta and amyloid beta 42 peptide is potentiated by hypoxia in primary human neural cells. J. Biol. Chem. 277, 30,359–30,367.CrossRefGoogle Scholar
  66. 66.
    Liao Y. F., Wang B. J., Cheng H. T., Kuo L. H., and Wolfe M. S. (2004) Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J. Biol. Chem. 279, 49,523–49,532.Google Scholar
  67. 67.
    Thompson P.M., Hayashi K.M., Sowell E.R., et al. (2004) Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia. Neuroimage 23(Suppl 1), S2-S18.PubMedCrossRefGoogle Scholar
  68. 68.
    Alexandrov P.N., Cui J.G., and Lukiw W. J. (2006) Hypoxia-sensitive domain in the human cytosolic phospholipase A2 promoter. Neuroreport 17, 303–307.PubMedCrossRefGoogle Scholar
  69. 69.
    Borenstein A.R., Copenhaver C.I., and Mortimer J.A. (2006) Early-life risk factors for Alzheimer disease. Alzheimer Dis. Assoc. Disord. 20, 63–72.PubMedCrossRefGoogle Scholar
  70. 70.
    Knopman D.S. (2006) Dementia and cerebrovascular disease. Mayo Clin. Proc. 81, 223–230.PubMedCrossRefGoogle Scholar
  71. 71.
    Griffin W.S. (2006) Inflammation and neurodegenerative diseases. Am. J. Clin. Nutr. 83, 470S-474S.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  1. 1.Neuroscience Center of ExcellenceLouisiana State University Health Sciences CenterNew Orleans

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