Neurovascular Mechanisms in Stroke, Neurodegeneration and Recovery

  • Lo, Eng-H. (Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School)
  • Published : 2006.10.01

Abstract

The emerging concept of the 'neurovascular unit' may enable a powerful paradigm shift for neuroscience. Instead of a pure focus on the 'neurobiology' of disease, an opportunity now exists to return to a more integrative approach. The neurovascular unit emphasizes that signaling between vascular and neuronal compartments comprise the basis for both function and dysfunction in brain. Hence, brain disorders are not just due to death of neurons, but instead manifested as cell signaling perturbations at the neurovascular interface. In this mini-review, we will examine 3 examples of this hypothesis: neurovascular mechanisms involved in the thrombolytic therapy of stroke, the crosstalk between neurogenesis and angiogenesis, and the link between vascular dysfunction and amyloid pathology in Alzheimer's disease. An understanding of cell-cell and cell-matrix signaling at the neurovascular interface may yield new approaches for targeting CNS disorders.

Keywords

References

  1. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7: 41-53, 2006 https://doi.org/10.1038/nrn1824
  2. Allan S. The neurovascular unit and the key role of astrocytes in the regulation of cerebral blood flow. Cerebrovasc Dis 21: 137- 138, 2006 https://doi.org/10.1159/000090447
  3. Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamaria E, Quintana M, Monasterio J, Montaner J. Temporal profile of mnatrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35: 1316-1322, 2004 https://doi.org/10.1161/01.STR.0000126827.69286.90
  4. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8: 963-970, 2002 https://doi.org/10.1038/nm747
  5. Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K+ and H+ at crttical levels of brain ischemia. Stroke 8: 51-57, 1977 https://doi.org/10.1161/01.STR.8.1.51
  6. Baranes D, Lederfein D, Huang YY, Chen M, Bailey C, Kandel E. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21: 813-825, 1998 https://doi.org/10.1016/S0896-6273(00)80597-8
  7. Benchenane K, Berezowski V, Ali C, Fernandez-Monreal M, Lopez- Atalaya JP, Brillault J, Chuquet J, Nouvelot A, MacKenzie ET, Bu G, Cecchelli R, Touzani O, Vivien D. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 111: 2241-2249, 2005 https://doi.org/10.1161/01.CIR.0000163542.48611.A2
  8. Benveniste H. The excitotoxin hypothesis in relation to cerebral ischemia. Cerebrovasc Brain Metab Rev 3: 213-220, 1991
  9. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegeneration. Nat Med 10 Suppl: S2-9, 2004 https://doi.org/10.1038/nm1067
  10. Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging 21: 153-160, 2000
  11. Buchan AM. Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? Cerebrovasc Brain Metab Rev 2: 1-26, 1990
  12. Carmeliet P. Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4: 710-720, 2003 https://doi.org/10.1038/nrg1158
  13. Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91: 917-925, 1997 https://doi.org/10.1016/S0092-8674(00)80483-3
  14. Davis J, Xu F, Deane R, Romanov G, Previti M, Zeigler K, Zlokovic BV, Van Nostrand WE. 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: 20296- 20306, 2004 https://doi.org/10.1074/jbc.M312946200
  15. De Keyser J, Sulter G, Luiten PG. Clinical trials with neuroprotective drugs in acute ischemic stroke: are we doing the right thing? Trends Neurosci 22: 535-540, 2000 https://doi.org/10.1016/S0166-2236(99)01463-0
  16. de la Torre JC. Alzheimer disease as a vascular disorder. Stroke 33: 1152-1162, 2002 https://doi.org/10.1161/01.STR.0000014421.15948.67
  17. Deane R, Wu Z, Sagare A, Davis J, Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu H, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43: 333-344, 2004 https://doi.org/10.1016/j.neuron.2004.07.017
  18. Deb S, Wenjun Zhang J, Gottschall PE. Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res 970: 205-213, 2003 https://doi.org/10.1016/S0006-8993(03)02344-8
  19. Dijkhuizen RM, Singhal AB, Mandeville J, Wu O, Halpern EF, Finklestein SP, Rosen BR, Lo EH. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J Neurosci 23: 510-517, 2003 https://doi.org/10.1523/JNEUROSCI.23-02-00510.2003
  20. Donahue JE, Flaherty SL, Johanson CE, Duncan JA 3rd, Silverberg GD, Miller MC, Tavares R, Yang W, Wu Q, Sabo E, Hovanesian V, Stopa EG. RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta Neuropathol (Berl), 112: 405-415, 2006 https://doi.org/10.1007/s00401-006-0115-3
  21. ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator in acute hemispheric stroke. JAMA 274: 1017-1025, 1995 https://doi.org/10.1001/jama.274.13.1017
  22. Eichmann A, Le Noble F, Autiero M, Carmeliet P. Guidance of vascular and neural network formation. Curr Opin Neurobiol 15: 108-115, 2005 https://doi.org/10.1016/j.conb.2005.01.008
  23. Garcia JH. Morphology of global cerebral ischemia. Crit Care Med 16: 979-987, 1988 https://doi.org/10.1097/00003246-198810000-00009
  24. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials. Stroke 33: 2123- 2136, 2002 https://doi.org/10.1161/01.STR.0000025518.34157.51
  25. Greenberg DA, Jin K. Neurodegeneration and neurogenesis: focus on Alzheimer's disease. Curr Alzheimer Res 3: 25-28, 2006 https://doi.org/10.2174/156720506775697106
  26. Greenberg SM. Cerebral amyloid angiopathy and dementia: two amyloids are worse than one. Neurology 58: 1587-1588, 2002 https://doi.org/10.1212/WNL.58.11.1587
  27. Gualadris A, Jones TE, Strickland S, Tsirka SE. Membrane deplorization induces calcium dependent secretion of tissue plasminogen activator. J Neurosci 16: 2220-2225, 1996 https://doi.org/10.1523/JNEUROSCI.16-07-02220.1996
  28. Guo S, Wang S, Km WJ, Lee S, Froesch MP, Bacskai BJ, Greenberg SM, Lo EH. Effects of ApoE isoforms on beta-amyloid-induced matrix metalloproteinase in rat astrocytes. Brain Res (in press), 2006
  29. Hacke W, Brott T, Caplan L, Meier D, Fieschi C, von Kummer R, Donnan G, Heiss WD, Wahlgren NG, Spranger M, Boysen G, Marler JR. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology 53 (Suppl 4): s3-s15, 1999 https://doi.org/10.1212/WNL.53.1.3
  30. Harukuni I, Bhardwaj A. Mechanisms of brain injury after global cerebral ischemia. Neurol Clin 24: 1-21, 2006 https://doi.org/10.1016/j.ncl.2005.10.004
  31. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57: 173-185, 2005 https://doi.org/10.1124/pr.57.2.4
  32. Hirose K, Chan PH. Blockade of glutamate excitotoxicity and its clinical applications. Neurochem Res 18: 479-483, 1993 https://doi.org/10.1007/BF00967252
  33. Hopewell JW, Cavanagh JB. Effects of X irradiation on the mitotic activity of the subependymal plate of rats. Br J Radiol 45: 461- 465, 1972 https://doi.org/10.1259/0007-1285-45-534-461
  34. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 5: 347-360, 2004 https://doi.org/10.1038/nrn1387
  35. Iadecola C, Zhang F, Niwa K, Eckman C, Turner S, Fischer E, Younkin S, Borchelt DR, Hsiao KK, Carlson GA. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 2: 157-161, 1999 https://doi.org/10.1038/5715
  36. Kaur J, Zhao Z, Klein GM, Lo EH, Buchan AM. The neurotoxicity of tissue plasminogen activator? J Cereb Blood Flow Metab 24: 945-963, 2004 https://doi.org/10.1097/01.WCB.0000137868.50767.E8
  37. Kim Y, Huang J, Lee SR, Tejima E, Mandeville J, van Meer M, Dai G, Choi YW, Dijkhuizen RM, Lo EH, Rosen BR. Measurements of BOLD/CBV ratios show altered hemodynamics during stroke recovery. J Cereb Blood Flow Metab 25: 820-829, 2005 https://doi.org/10.1038/sj.jcbfm.9600084
  38. Kim YR, van Meer MP, Mandeville JB, Tejima E, Dai G, Topalkara K, Qui J, Dijkhuizen RM, Moskowitz MA, Lo EH, Rosen BR. fMRI of delayed albumin treatment during stroke recovery in rats: implication for fast neuronal habituation in recovering brains. J Cereb Blood Flow Metab (in press), 2006
  39. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (Tissue plasminogen Activator)-induced hemorrhage after thromboembolic stroke. Stroke 31: 3034- 3040, 2000 https://doi.org/10.1161/01.STR.31.12.3034
  40. Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J. Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann Neurol 54: 379-382, 2003 https://doi.org/10.1002/ana.10671
  41. Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM, Lo EH. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26: 3491-3495, 2006 https://doi.org/10.1523/JNEUROSCI.4085-05.2006
  42. Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci 13: 450- 464, 1999 https://doi.org/10.1006/mcne.1999.0762
  43. Lewis PD. Radiosensitivity of the subependymal cell layer of the adult rat brain. Exp Neurol 20: 208-214, 1968 https://doi.org/10.1016/0014-4886(68)90094-0
  44. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330: 613-622, 1994 https://doi.org/10.1056/NEJM199403033300907
  45. Liu J, Solway K, Messing RO, Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils J Neurosci 18: 7768-7778, 1998 https://doi.org/10.1523/JNEUROSCI.18-19-07768.1998
  46. Lo EH, Broderick JP, Moskowitz MA. tPA and proteolysis in the neurovascular unit. Stroke 35: 354-356, 2004 https://doi.org/10.1161/01.STR.0000115164.80010.8A
  47. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 430: 631-639, 2004 https://doi.org/10.1038/nature02621
  48. McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet 22: 281-289, 2006 https://doi.org/10.1016/j.tig.2006.03.007
  49. Montaner J, Alvarez-Sabin J, Molina CA, Angles A, Abilleira S, Arenillas J, Monasterio J. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 32: 2762-2767, 2001 https://doi.org/10.1161/hs1201.99512
  50. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J. Matrix metalloproteinase- 9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107: 598-603, 2003 https://doi.org/10.1161/01.CIR.0000046451.38849.90
  51. Nassar T, Akkawi S, Shina A, Haj-Yehia A, Bdeir K, Tarshis M, Heyman SN, Higazi AA. In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone. Blood 103: 897-902, 2004 https://doi.org/10.1182/blood-2003-05-1685
  52. Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue plasminogen activator enhances NMDA receptor mediated signaling. Nature Med 7: 59-64, 2001 https://doi.org/10.1038/83358
  53. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 333: 1581-1587, 1995 https://doi.org/10.1056/NEJM199512143332401
  54. Ning M, Furie KL, Koroshetz WJ, Lee H, Barron M, Lederer M, Wang X, Zhu M, Sorensen AG, Lo EH, Kelly PJ. Association between tPA therapy and raised early matrix metalloproteinase- 9 in acute stroke. Neurology 66: 1550-1555, 2006 https://doi.org/10.1212/01.wnl.0000216133.98416.b4
  55. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 9: 61- 68, 2002a https://doi.org/10.1006/nbdi.2001.0460
  56. Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C. Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol 283: H315-H323, 2002b https://doi.org/10.1152/ajpcell.00544.2001
  57. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425: 479-494, 2000 https://doi.org/10.1002/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3
  58. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52: 802-813, 2002 https://doi.org/10.1002/ana.10393
  59. Park JA, Choi KS, Kim SY, Kim KW. Coordinated interaction of the vascular and nervous systems: from molecule- to cell-based approaches. Biochem Biophys Res Commun 311: 247-253, 2003 https://doi.org/10.1016/j.bbrc.2003.09.129
  60. Park L, Anrather J, Forster C, Kazama K, Carlson GA, Iadecola C. Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J Cereb Blood Flow Metab 24: 334-342, 2004 https://doi.org/10.1097/01.WCB.0000105800.49957.1E
  61. Paschen W. Glutamate excitotoxicity in transient global cerebral ischemia. Acta Neurobiol Exp (Wars) 56: 313-322, 1996
  62. Privat A, Leblond CP. The subependymal layer and neighboring region in the brain o the young rat. J Comp Neurol 146: 277- 302, 1972 https://doi.org/10.1002/cne.901460302
  63. Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 25: 641-650, 2004 https://doi.org/10.1016/j.neurobiolaging.2003.12.023
  64. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255: 1707-1710, 1992 https://doi.org/10.1126/science.1553558
  65. Rogove A, Siao CJ, Keyt B, Strickland S, Tsirka S. Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system. J Cell Sci 112: 4007-4016, 1999
  66. Rosell A, Ortega-Aznar A, Alvarez-Sabin J, Fernandez-Cadenas I, Ribo M, Molina CA, Lo EH, Montaner J. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 37: 1399-1406, 2006 https://doi.org/10.1161/01.STR.0000223001.06264.af
  67. Ryder EF, Snyder EY, Cepko CL. Establishment and characterization of multipotent neural cell lines using retrovirus vectormediated oncogene transfer. J Neurobiol 21: 356-375, 1990 https://doi.org/10.1002/neu.480210209
  68. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399: A23-A31, 1999 https://doi.org/10.1038/19866
  69. Shen Q, Goderie S, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304: 1338-1340, 2004 https://doi.org/10.1126/science.1095505
  70. Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D. Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol 2: 506-511, 2003 https://doi.org/10.1016/S1474-4422(03)00487-3
  71. Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis- associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33: 831-836, 2002 https://doi.org/10.1161/hs0302.104542
  72. Tejima E, Zhao BQ, Tsuji K, Rosell A, van Leyen K, Gonzalez RG, Montaner J, Wang X, Lo EH. Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab, 2006
  73. Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin induced neuronal degenaration and seizures are mediated by TPA. Nature 377: 340-344, 1995 https://doi.org/10.1038/377340a0
  74. Tsirka SE, Rogove AD, Strickland S. Neuronal cell death and TPA. Nature 384: 123-124, 1996
  75. Tsuji K, Aoki T, Tejima E, Arai K, Lee SR, Atochin DN, Huang PL, Wang X, Montaner J, Lo EH. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke 36: 1954-1959, 2005 https://doi.org/10.1161/01.STR.0000177517.01203.eb
  76. Vagnucci AH Jr, Li WW. Alzheimer's disease and angiogenesis. Lancet 361: 605-608, 2003 https://doi.org/10.1016/S0140-6736(03)12521-4
  77. Wang J, Rogove AD, Tsirka AE, Tsirka SE. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol 54: 655-664, 2003a https://doi.org/10.1002/ana.10750
  78. Wang X, Arai K, Lee SR, Lee S, Tsuji K, Rebeck GW, Lo EH. Lipoprotein receptor-mediated induction of matrix metalloproteinase- 9 in human cerebral endothelial cells. Nature Med 9: 1313-1319, 2003b https://doi.org/10.1038/nm926
  79. Wang YF, Tsirka SE, Strickland S, Steig PE, Soriano SG, Lipton SA. TPA increases neuronal damage after focal cerebral ischemia in wild type and TPA-deficient mice. Nature Med 4: 228- 231, 1998 https://doi.org/10.1038/nm0298-228
  80. Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 35: 2659-2661, 2004 https://doi.org/10.1161/01.STR.0000144051.32131.09
  81. Ward NL, Lamanna JC. The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res 26: 870-883, 2004 https://doi.org/10.1179/016164104X3798
  82. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9: 453-457, 2003 https://doi.org/10.1038/nm838
  83. Xu J, Chen S, Ku G, Ahmed SH, Xu J, Chen H, Hsu CY. Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21: 702-710, 2001 https://doi.org/10.1097/00004647-200106000-00008
  84. Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281: 24566-24574, 2006 https://doi.org/10.1074/jbc.M602440200
  85. Yin KJ, Lee JM, Chen SD, Xu J, Hsu CY. Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. J Neurosci 22: 9764-9770, 2002 https://doi.org/10.1523/JNEUROSCI.22-22-09764.2002
  86. Yin KJ, Lee JM, Chen H, Xu J, Hsu CY. Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells. J Cereb Blood Flow Metab 25: 1445-1455, 2005 https://doi.org/10.1038/sj.jcbfm.9600139
  87. Zhang RL, Zhang ZG, Zhang L, Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105: 33-41, 2001 https://doi.org/10.1016/S0306-4522(01)00117-8
  88. Zhang-Nunes SX, Maat-Schieman ML, van Duinen SG, Roos RA, Frosch MP, Greenberg SM. The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16: 30-39, 2006 https://doi.org/10.1111/j.1750-3639.2006.tb00559.x
  89. Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12: 441-445, 2006 https://doi.org/10.1038/nm1387
  90. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 28: 202-208, 2005 https://doi.org/10.1016/j.tins.2005.02.001