Neurovascular regulation in the normal brain and in Alzheimer's disease

Nature Reviews Neuroscience

Volumn 5, Issue 5, 2004, Pages 347-360

  Iadecola, Costantino ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE; ADENOSINE RECEPTOR; CYTOCHROME P450 INHIBITOR; EPOXYICOSATRIENOIC ACID; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; PROSTAGLANDIN SYNTHASE;

ALZHEIMER DISEASE; ASTROCYTE; BRAIN BLOOD FLOW; BRAIN BLOOD VESSEL; BRAIN FUNCTION; BRAIN MICROCIRCULATION; BRAIN REGION; CLINICAL PATHWAY; CONTROL SYSTEM; FUNCTIONAL ANATOMY; HEMOSTASIS; HUMAN; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SIGNAL PROCESSING;

EID: 2342614850     PISSN: 1471003X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrn1387     Document Type: Review

References (183)

1. Hossmann, K.-A. Viability thresholds and the penumbra of focal ischemia. Ann. Neurol. 36, 557-565 (1994). This paper provides an appraisal of the effects of reduction in CBF on brain metabolism and function.
2. Van Lieshout, J. J., Wieling, W., Karemaker, J. M. & Secher, N. H. Syncope, cerebral perfusion, and oxygenation. J. Appl. Physiol. 94, 833-848 (2003).
3. Imai, Y., Ohkubo, T., Tsuji, I., Satoh, H. & Hisamichi, S. Clinical significance of nocturnal blood pressure monitoring. Clin. Exp. Hypertens. 21, 717-727 (1999).
4. Sander, D., Winbeck, K., Klingelhofer, J. & Conrad, B. Extent of cerebral white matter lesions is related to changes of circadian blood pressure rhythmicity. Arch. Neurol. 57, 1302-1307 (2000).
5. Heistad, D. & Kontos, H. in Handbook of Physiology: The Cardiovascular System III (eds Abboud, F. & Shephard, J.) 137-182 (American Physiological Society, Bethesda, 1983). An in-depth discussion of cerebrovascular autoregulation and a comprehensive review of the cerebrovascular literature up to the early 1980s.
6. Logothetis, N. K. The underpinnings of the BOLD functional magnetic resonance imaging signal. J. Neurosci. 23, 3963-3971 (2003). An accurate and approachable presentation of the neurophysiological bases of the BOLD signal.
7. Mathiesen, C., Caesar, K., Akgoren, N. & Lauritzen, M. Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex. J. Physiol. (Lond.) 512, 555-566 (1998).
8. Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150-157 (2001). References 7 and 8 provide evidence that spiking activity and CBF are not necessarily linked.
9. Caesar, K., Thomsen, K. & Lauritzen, M. Dissociation of spikes, synaptic activity, and activity-dependent increments in rat cerebellar blood flow by tonic synaptic inhibition. Proc. Natl Acad. Sci. USA 100, 16000-16005 (2003).
10. Mosso, A. Sulla circolazione del cervello dell'uomo. Atti R. Accad. Lincei 5, 237-358 (1880).
11. Iadecola, C. Regulation of the cerebral microcirculation during neural activity: is nitric oxide the missing link? Trends Neurosci. 16, 206-214 (1993).
12. Roy, C. & Sherrington, C. On the regulation of the blood-supply of the brain. J. Physiol. (Lond.) 11, 85-108 (1890).
13. Heuser, D. in Cerebral Vascular Smooth Muscle and its Control (eds Elliot, K. & O'Connor, M.) 339-353 (Elsevier, New York, 1978).
14. Uddman, R. & Edvinsson, L. Neuropeptides in the cerebral circulation. Cerebrovasc. Brain Metab. Rev. 1, 230-252 (1989).
15. Edvinsson, L. & Krause, D. N. in Cerebral Blood Flow and Metabolism (eds Edvinsson, L. & Krause, D. N.) 191-211 (Lippincott, Williams and Wilkins, Philadelphia, 2002). A comprehensive source eddressing the main aspects of the structure and function of the cerebral circulation.
16. Fergus, A. & Lee, K. S. GABAergic regulation of cerebral microvascular tone in the rat. J. Cereb. Blood Flow Metab. 17, 992-1003 (1997).
17. Hamel, E. Cholinergic modulation of the cortical microvascular bed. Prog. Brain. Res. 145, 171-178 (2004).
18. Faraci, F. M. & Breese, K. R. Nitric oxide mediates vasodilation in response to activation of N-methyl-D-aspartate receptors in brain. Circ. Res. 72, 476-480 (1993). This paper first implicated NO in the mechanisms of the increase in CBF produced by activation of NMDA receptors.
19. Bhardwaj, A. et al. P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-D-aspartate. Am. J. Physiol. Heart Circ. Physiol. 279, H1616-1624 (2000).
20. Buerk, D. G., Ances, B. M., Greenberg, J. H. & Detre, J. A. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18, 1-9 (2003).
21. Niwa, K., Araki, E., Morham, S. G., Ross, M. E. & Iadecola, C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J. Neurosci. 20, 763-770 (2000).
22. Iliff, J. J., D'Ambrosio, R., Ngai, A. C. & Winn, H. R. Adenosine receptors mediate glutamate-evoked arteriolar dilation in the rat cerebral cortex. Am. J. Physiol. Heart Circ. Physiol. 284, H1631-1637 (2003).
23. Lassen, N. A. Brain extracellular pH: the main factor controlling cerebral blood flow. Scand. J. Clin. Lab. Invest. 22, 247-251 (1968).
24. Plum, F. in Cerebral Vascular Smooth Muscle and its Control (eds Elliot, K. & O'Connor, M.) 3-7 (Elsevier, New York, 1978).
25. Ko, K. R., Ngai, A. C. & Winn, R. H. Role of adenosine in regulation of regional cerebral blood flow in sensory cortex. Am. J. Physiol. 259, H1703-H1708 (1990).
26. Peng, X. et al. Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am. J. Physiol. Heart Circ. Physiol. 283, H2029-2037 (2002).
27. Dirnagl, U., Lindauer, U. & Villringer, A. Role of nitric oxide in the coupling of cerebral blood flow to neural activation in rats. Neurosci. Lett. 149, 43-46 (1993).
28. Yang, G., Chen, G., Ebner, T. J. & Iadecola, C. Nitric oxide is the predominant mediator of cerebellar hyperemia during somatosensory activation in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 277 R1760-R1770 (1999).
29. Hayashi, T. et al. Neuronal nitric oxide has a role as a perfusion regulator and a synaptic modulator in cerebellum but not in neocortex during somatosensory stimulation - an animal PET study. Neurosci. Res. 44, 155-165 (2002).
30. Ma, J., Ayata, C., Huang, P. L., Fishman, M. C. & Moskowitz, M. A. Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. Am. J. Physiol. Heart. Circ. Physiol. 270 H1085-1090 (1996).
31. Yang, G., Zhang, Y., Ross, M. E. & Iadecola, C. Attenuation of activity-induced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase. Am. J. Physiol. Heart. Circ. Physiol. 285, H298-304 (2003).
32. Cholet, N., Seylaz, J., Lacombe, P. & Bonvento, G. Local uncoupling of the cerebrovascular and metabolic responses to somatosensory stimulation after neuronal nitric oxide synthase inhibition. J. Cereb. Blood Flow Metab. 17, 1191-1201 (1997).
33. Gotoh, J. et al. Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am. J. Physiol. Heart. Circ. Physiol. 280, H821-829 (2001).
34. Ances, B. M., Buerk, D. G., Greenberg, J. H. & Detre, J. A. Temporal dynamics of the partial pressure of brain tissue oxygen during functional forepaw stimulation in rats. Neurosci. Lett. 306, 106-110 (2001).
35. Cooper, R. S., Papakostopoulos, D. & Crow, H. J. in Blood Flow and Metabolism in the Brain (eds Harper, A. M., Jennett, B., Miller, D. L. & Rowan, J.) 14.8-14.9 (Churchill Livingstone, New York, 1975).
36. Vanzetta, I. & Grinvald, A. Increased cortical oxidative metabolism due to sensory stimulation: implications for functional brain imaging. Science 286, 1555-1558 (1999).
37. Ances, B. M. Coupling of changes in cerebral blood flow with neural activity: what must initially dip must come back up. J. Cereb. Blood Flow Metab. 24, 1-6 (2004).
38. Mintun, M. A. et al. Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data. Proc. Natl Acad. Sci. USA 98, 6859-6864 (2001).
39. Powers, W. J., Hirsch, I. B. & Cryer, P. E. Effect of stepped hypoglycemia on regional cerebral blood flow response to physiological brain activation. Am. J. Physiol. 270, H554-559 (1996).
40. Attwell, D. & Iadecola, C. The neural basis of functional brain imaging signals. Trends Neurosci 25, 621-615 (2002). This review proposes that the increase in CBF evoked by activation is linked to synaptic signalling rather than to the metabolic needs of the tissue.
41. Mintun, M. A., Vlassenko, A. G., Rundle, M. M. & Raichle, M. E. Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proc. Natl Acad. Sci. USA 101, 659-664 (2004).
42. Ido, Y., Chang, K. & Williamson, J. R. NADH augments blood flow in physiologically activated retina and visual cortex. Proc. Natl Acad. Sci. USA 101, 653-648 (2004).
43. Ido, Y., Chang, K., Woolsey, T. A. & Williamson, J. R. NADH: sensor of blood flow need in brain, muscle, and other tissues. Faseb J. 15, 1419-1421 (2001).
44. Silva, A. C. & Koretsky, A. P. Laminar specificity of functional MRI onset times during somatosensory stimulation in rat. Proc. Natl Acad. Sci. USA 99, 15182-15187 (2002).
45. Norup Nielsen, A. & Lauritzen, M. Coupling and uncoupling of activity-dependent increases of neuronal activity and blood flow in rat somatosensory cortex. J. Physiol. (Lond.) 533, 773-785 (2001).
46. Chaigneau, E., Oheim, M., Audinat, E. & Charpak, S. Two-photon imaging of capillary blood flow in olfactory bulb glomeruli. Proc. Natl Acad. Sci. USA 100, 13081-13086 (2003). This paper provides striking evidence of the spatial accuracy of the changes in CBF produced by neural activity.
47. Freund, T. F. Interneuron diversity series: rhythm and mood in perisomatic inhibition. Trends Neurosci. 26, 489-495 (2003).
48. Cauli, B., Tong, X. K., Lambolez, B., Rossier, J. & Hamel, E. Stimulation of distinct populations of GABA intemeurons elicits changes in local microvessel diameter in the rat cerebral cortex. Soc. Neurosci. Abstr. 889.13 (2003).
49. Iadecola, C., Arneric, S., Baker, H., Tucker, L. & Reis, D. Role of local neurons in the cerebrocortical vasodilation elicited from cerebellum. Am. J. Physiol. Regul. Integr. Comp. Physiol. 252, R1082-1091 (1987).
50. Iadecola, C., Li, J., Yang, G. & Xu, S. Neural mechanisms of blood flow regulation during synaptic activity in cerebellar cortex. J. Neurophysiol. 75, 940-950 (1996).
51. Yang, G., Huard, J. M., Beitz, A. J., Ross, M. E. & Iadecola, C. Stellate neurons mediate functional hyperemia in the cerebellar molecular layer. J. Neurosci. 20, 6968-6973 (2000). This paper provides direct evidence that cerebellar interneurons control local blood flow.
52. Wu, D. M., Kawamura, H., Sakagami, K., Kobayashi, M. & Puro, D. G. Cholinergic regulation of pericyte-containing retinal microvessels. Am. J. Physiol. Heart Circ. Physiol. 284, H2083-2090 (2003).
53. Nedergaard, M. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 28, 523-530 (2003).
54. Paulson, O. B. & Newman, E. A. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237, 896-898 (1987).
55. Harder, D. R., Zhang, C. & Gebremedhin, D. Astrocytes function in matching blood flow to metabolic activity. News Physiol. Sci. 17, 27-31 (2002).
56. Rosenblum, W. Cerebral microcirculation: a review emphasizing the interrelationship of local blood flow and neuronal function. Angiology 16, 485-507 (1965).
57. Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43-50 (2003). This paper provides evidence that calcium changes in astrocytic end-feet control local vascular resistance.
58. Zonta, M. et al. Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J. Physiol. (Lond.) 553, 407-414 (2003).
59. Duling, B. R. et al. Vasomotor control: functional hyperemia and beyond. Federation Proc. 46, 251-263 (1987).
60. Cox, S. B., Woolsey, T. A. & Rovainen, C. M. Localized dynamic changes in cortical blood flow with whisker stimulation corresponds to matched vascular and neuronal architecture of rat barrels. J. Cereb. Blood Flow Metab. 13, 899-913 (1993).
61. Erinjeri, J. P. & Woolsey, T. A. Spatial integration of vascular changes with neural activity in mouse cortex. J. Cereb. Blood Flow Metab. 22, 353-360 (2002).
62. Ngai, A. C., Ko, K. R., Modi, S. & Winn, H. R. Effect of sciatic nerve stimulation on pial arterioles in rats. Am. J. Physiol. 254, H133-139 (1988).
63. Iadecola, C., Yang, G., Ebner, T. & Cheng, G. Local and propagated vascular responses evoked by focal synaptic activity in cerebellar cortex. J. Neurophysiol. 78, 651-659 (1997).
64. Ibayashi, S. et al. Lack of sympathetic and cholinergic influences on the cerebral vasodilation caused by sciatic nerve stimulation in the rat. J. Cereb. Blood Flow Metab. 11, 678-683 (1991).
65. Dietrich, H. H., Kajita, T. & Dacey, R. G. Local and conducted vasomotor responses in isolated rat cerebral arterioles. Am. J. Physiol. Heart Circ. Physiol. 271, H1109-1116 (1996).
66. Fujii, K., Faraci, F. & Heistad, D. D. Flow-mediated vasodilation of the basilar artery in vivo. Circ. Res. 69, 697-705 (1991).
67. Busse, R. & Fleming, I. Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol. Sci. 24, 24-29 (2003).
68. Iadecola, C. in Cerebrovascular Diseases (eds Ginsberg, M. D. & Bogousslavsky, J.) 319-332 (Blackwell Science, Cambridge, Massachusetts, 1998).
69. Faraci, F. M. & Heistad, D. D. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol. Rev. 78, 53-97 (1998). This review provides a detailed account of the endothelial regulation of the cerebral circulation.
70. Mayhan, W. G. Cerebral circulation during diabetes mellitus. Pharmacol. Ther. 57, 377-391 (1993).
71. Kazama, K., Wang, G., Frys, K., Anrather, J. & Iadecola, C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am. J. Physiol. Heart Circ. Physiol. 285, H1890-1899 (2003).
72. Kudo, T. et al. Are cerebrovascular factors involved in Alzheimer's disease? Neurobiol. Aging 21, 215-224 (2000).
73. de la Torre, J. C. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33, 1152-1162 (2002). References 73, 74 and 89 summarize the evidence that vascular factors might contribute to AD.
74. Kalaria, R. N. The role of cerebral ischemia in Alzheimer's disease. Neurobiol. Aging 21, 321-330 (2000).
75. Morris, J. C. Dementia update 2003. Alzheimer Dis. Assoc. Disord. 17, 245-258 (2003).
76. Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121-1159 (2001).
77. Selkoe, D. J. & Schenk, D. Alzheimer's Disease: molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 43, 545-584 (2003).
78. Glenner, G. G. & Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885-890 (1984).
79. Glenner, G. G. & Wong, C. W. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131-1135 (1984).
80. Roher, A. E. et al. β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 10836-10840 (1993).
81. Price, D. L. & Sisodia, S. S. Mutant genes in familial Alzheimer's disease and transgenic models. Annu. Rev. Neurosci. 21, 479-505 (1998).
82. Mattson, M. P. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081-1132 (1997). A comprehensive review of the cellular biology of Aβ.
83. Christie, R., Yamada, M., Moskowitz, M. & Hyman, B. Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am. J. Pathol. 158, 1065-1071 (2001).
84. Abramov, A. Y., Canevari, L. & Duchen, M. R. β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J. Neurosci. 24, 565-575 (2004).
85. Yin, K. J., Lee, J. M., Chen, S. D., Xu, J. & Hsu, C. Y. Amyloid-β induces Smac release via AP-1/Bim activation in cerebral endothelial cells. J. Neurosci. 22, 9764-9770 (2002).
86. Lee, J. T. et al. Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J. Cell Biol. 164, 123-131 (2004).
87. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383-388 (1991).
88. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939-944 (1984).
89. Farkas, E. & Luiten, P. G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575-611 (2001).
90. Brun, A. & Englund, E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann. Neurol. 19, 253-262 (1986).
91. Lee, B. C., Mintun, M., Buckner, R. L. & Morris, J. C. Imaging of Alzheimer's disease. J. Neuroimaging 13, 199-214 (2003).
92. Rapoport, S. I. Functional brain imaging to identify affected subjects genetically at risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 97, 5696-5698 (2000).
93. Jagust, W. J. Neuroimaging in dementia. Neurol. Clin. 18, 885-902 (2000).
94. Snowdon, D. A. Healthy aging and dementia: findings from the Nun Study. Ann. Intern. Med. 139, 450-454 (2003).
95. Roher, A. E. et al. Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer's disease. Arterioscler. Thromb. Vasc. Biol. 23, 2055-2062 (2003).
96. Iadecola, C. Atherosclerosis and neurodegeneration: unexpected conspirators in Alzheimer's dementia. Arterioscler. Thromb. Vasc. Biol. 23, 1951-1953 (2003).
97. Thomas, T., Thomas, G., McLendon, C., Sutton, T. & Mullan, M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168-171 (1996). This paper provided the first evidence that Aβ influences vascular reactivity and that the effect is mediated by free radicals.
98. Crawford, F., Suo, Z., Fang, C. & Mullan, M. Characteristics of the in vitro vasoactivity of β-amyloid peptides. Exp. Neurol. 150, 159-168 (1998).
99. Paris, D. et al. Vasoactive effects of Aβ in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol. Res. 25, 642-651 (2003).
100. Niwa, K. et al. Aβ-peptides enhance vasoconstriction in cerebral circulation. Am. J. Physiol. Heart Circ. Physiol. 281, H2417-2424 (2001).
101. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
102. Westerman, M. A. et al. The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 22, 1858-1867 (2002).
103. Kawarabayashi, T. et al. Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 372-381 (2001).
104. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nature Neurosci. 2, 157-161 (1999). This paper demonstrates that mice overexpressing App have altered endothellum-dependent CBF responses because of vascular oxidative stress.
105. Niwa, K. et al. Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am. J. Physiol. Heart. Circ. Physiol. 283, H315-323 (2002).
106. 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl Acad. Sci. USA 97, 9735-9740 (2000). This paper provided the first demonstration that Aβ inhibits functional hyperaemia in mice overexpressing App.
107. 1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J. Cereb. Blood Flow Metab. 20, 1659-1668 (2000).
108. Deane, R. et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Med. 9, 907-913 (2003). References 108 and 112 demonstrate that Aβ is transported across the blood-brain barrier in both directions, indicating that CBF can contribute to brain Aβ accumulation and/or clearance.
109. 40 in affected vessels. J. Neuropathol. Exp. Neurol. 57, 353-359 (1998).
110. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486-489 (2003).
111. Klein, W. L., Krafft, G. A. & Finch, C. E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219-224 (2001).
112. DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M. & Holtzman, D. M. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264-2267 (2002).
113. Zhang, F., Eckman, C., Younkin, S., Hsiao, K. K. & Iadecola, C. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J. Neurosci. 17, 7655-7661 (1997).
114. Koistinaho, M. et al. β-amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc. Natl Acad. Sci. USA 99, 1610-1615 (2002).
115. De Meyer, G. R. et al. Platelet phagocytosis and processing of β-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ. Res. 90, 1197-1204 (2002).
116. Moore, K. J. et al. A CD36-initiated signaling cascade mediates inflammatory effects of β-amyloid. J. Biol. Chem. 277, 47373-47379 (2002).
117. Wolozin, B. Cholesterol and the biology of Alzheimer's disease. Neuron 41, 7-10 (2004).
118. Van Nostrand, W. E., Schmaier, A. H., Farrow, J. S. & Cunningham, D. D. Protease nexin-II (amyloid β-protein precursor): a platelet α-granule protein. Science 248, 745-748 (1990).
119. Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47-95 (2002).
120. Park, L. et al. Aβ-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J. Cereb. Blood Flow Metab. 24, 334-342 (2004).
121. Faraci, F. M. Hyperhomocysteinemia: a million ways to lose control. Arterioscler. Thromb. Vasc. Biol. 23, 371-373 (2003).
122. Cai, H., Griendling, K. K. & Harrison, D. G. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol. Sci. 24, 471-478 (2003).
123. Iadecola, C. & Gorelick, P. B. Hypertension, angiotensin, and stroke: beyond blood pressure. Stroke 35, 348-350 (2004).
124. Della Bianca, V., Dusi, S., Bianchini, E., Dal Pra, I. & Rossi, F. β-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, 15493-15499 (1999).
125. Parvathenani, L. K. et al. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease. J. Biol. Chem. 278, 13309-13317 (2003).
126. Shimohama, S. et al. Activation of NADPH oxidase in Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 273, 5-9 (2000).
127. Hensley, K. et al. A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 3270-3274 (1994).
128. Zou, M. H., Leist, M. & Ullrich, V. Selective nitration of prostacyclin synthase and defective vasorelaxation in atherosclerotic bovine coronary arteries. Am. J. Pathol. 154, 1359-1365 (1999).
129. Guo, W. et al. Quantitative assessment of tyrosine nitration of manganese superoxide dismutase in angiotensin II-infused rat kidney. Am. J. Physiol. Heart Circ. Physiol. 285, H1396-1403 (2003).
130. Soriano, F. G., Virag, L. & Szabo, C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation. J. Mol. Med. 79, 437-448 (2001).
131. Katusic, Z. S. Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am. J. Physiol. Heart Circ. Physiol. 281, H981-986 (2001).
132. Walsh, D. M. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539 (2002).
133. Ikegaya, Y. et al. β-amyloid enhances glial glutamate uptake activity and attenuates synaptic efficacy. J. Biol. Chem. 277, 32180-32186 (2002).
134. Tong, X. K. & Hamel, E. Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease. Neuroscience 92, 163-175 (1999).
135. Abe, K., Tanzi, R. E. & Kogure, K. Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischemia in rat cerebral cortex. Neurosci. Lett. 125, 172-174 (1991).
136. Uryu, K. et al. Repetitive mild brain trauma accelerates Aβ deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J. Neurosci. 22, 446-454 (2002).
137. Yokota, M., Saido, T. C., Tani, E., Yamaura, I. & Minami, N. Cytotoxic fragment of amyloid precursor protein accumulates in hippocampus after global forebrain ischemia. J. Cereb. Blood Flow Metab. 16, 1219-1223 (1996).
138. Hartlage-Rubsamen, M. et al. Astrocytic expression of the Alzheimer's disease β-secretase (BACE1) is stimulus-dependent. Glia 41, 169-179 (2003).
139. Smith, C. D. et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology 53, 1391-1396 (1999).
140. Bookheimer, S. Y. et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450-456 (2000).
141. Mentis, M. J. et al. Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation. Am. J. Psychiatr. 155, 785-794 (1998).
142. Mies, G., Ishimaru, S., Xie, Y., Seo, K. & Hossmann, K. A. Ischemic thresholds of cerebral protein synthesis and energy state following middle cerebral artery occlusion in rat. J. Cereb. Blood Flow Metab. 11, 753-761 (1991).
143. Martin, K. C., Barad, M. & Kandel, E. R. Local protein synthesis and its role in synapse-specific plasticity. Curr. Opin. Neurobiol. 10, 587-592 (2000).
144. Debiec, J., LeDoux, J. E. & Nader, K. Cellular and systems reconsolidation in the hippocampus. Neuron 36, 527-538 (2002).
145. Kleim, J. A. et al. Functional organization of adult motor cortex is dependent upon continued protein synthesis. Neuron 40, 167-176 (2003).
146. Moody, D. M., Bell, M. A. & Challa, V. R. Features of the cerebral vascular pattern that predict vulnerability to perfusion or oxygenation deficiency: an anatomic study. Am. J. Neuroradiol. 11, 431-439 (1990).
147. Matsushita, K. et al. Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension 23, 565-568 (1994).
148. Barber, R. et al. White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dernentia, and normal aging. J. Neurol. Neurosurg. Psychiatr. 67, 66-72 (1999).
149. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nature Genet. 35, 131-138 (2003).
150. Lo, E. H., Dalkara, T. & Moskowitz, M. A. Mechanisms, challenges and opportunities in stroke. Nature Rev. Neurosci. 4, 399-415 (2003). A critical appraisal of the mechanisms of cerebral ischaemia with emphasis on the neurovascular unit.
151. Mosso, A. Ueber den Kreislauf des Blutes im Menschlichen Gehim (Viet, Leipzig, 1881).
152. Mosso, A. La Temperatura del Cervello (Fratelli Treves, Milano, 1894).
153. Kety, S. S. & Schmidt, C. F. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values. J. Clin. Invest. 27, 476-483 (1948).
154. Lassen, N. A. & Ingvar, D. H. The blood flow of the cerebral cortex determined by radioactive krypton. Experientia 17, 42-43 (1961).
155. Raichle, M. E. in The Nervous System. Volume 5: Higher Functions of the Brain, Part 2 (ed Plum, F.) 643-674 (American Physiological Society, Bethesda, 1987).
156. Fox, P. T. & Raichle, M. E. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc. Natl Acad. Sci. USA 83, 1140-1144 (1986).
157. Fox, P. T., Raichle, M. E., Mintun, M. A. & Dence, C. Nonoxidative glucose consumption during focal physiological neural activity. Science 241, 462-464 (1988).
158. Ogawa, S., Lee, T. M., Kay, A. R. & Tank, D. W. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc. Natl Acad. Sci. USA 87, 9868-9872 (1990).
159. Ogawa, S. et al. Intrinsic signal changes accompanying sensory stimulation: Functional brain mapping with magnetic resonance imaging. Proc. Natl Acad. Sci. USA 89, 5951-5955 (1992).
160. Kwong, K. K. et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc. Natl Acad. Sci. USA 89, 5675-5679 (1992).
161. Bandettini, P. A., Wong, E. C., Hinks, R. S., Tikofsky, R. S. & Hyde, J. S. Time course EPI of human brain function during task activation. Magn. Reson. Med. 25, 390-397 (1992).
162. Ugurbil, K., Toth, L. & Kim, D. S. How accurate is magnetic resonance imaging of brain function? Trends Neurosci. 26, 108-114 (2003).
163. Woolsey, T. A. et al. Neuronal units linked to microvascular modules in cerebral cortex: response elements for imaging the brain. Cereb. Cortex 6, 647-660 (1996).
164. Stroke Progress Review Group. Report of the Stroke Progress Review Group (National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, 2002). This report outlines outstanding issues and future directions in research that is related to cerebrovascular diseases and stroke.
165. del Zoppo, G. J. & Mabuchi, T. Cerebral microvessel responses to focal ischemia. J. Cereb. Blood Flow Metab. 23, 879-894 (2003). An insightful review of the changes that cerebral ischaemia induces in the neurovascular unit.
166. Jones, E. G. On the mode of entry of blood vessels into the cerebral cortex. J. Anat. 106, 507-520 (1970). References 166 and 174 provide a detailed description of the relationship between penetrating cerebral blood vessels and brain cells.
167. Peters, A., Palay, S. & Webster, H. D. The Fine Structure of the Nervous System (Oxford University Press, New York, 1991).
168. Golding, E. M., Marrelli, S. P., You, J. & Bryan, R. M. Jr. Endothelium-derived hyperpolarizing factor in the brain: a new regulator of cerebral blood flow? Stroke 33, 661-663 (2002).
169. Segal, S. S. Integration of blood flow control to skeletal muscle: key role of feed arteries. Acta Physiol. Scand. 168, 511-518 (2000).
170. Somlyo, A. P., Wu, X., Walker, L. A. & Somlyo, A. V. Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev. Physiol. Biochem. Pharmacol. 134, 201-234 (1999).
171. Prewitt, R. L., Rice, D. C. & Dobrian, A. D. Adaptation of resistance arteries to increases in pressure. Microcirculation 9, 295-304 (2002).
172. Lagaud, G., Karicheti, V., Knot, H. J., Christ, G. J. & Laher, I. Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am. J. Physiol. Heart Circ. Physiol. 283, H2177-2186 (2002).
173. Kawamura, H. et al. ATP: a vasoactive signal in the pericyte-containing microvasculature of the rat retina. J. Physiol. (Lond.) 551, 787-799 (2003).
174. Maynard, E. A., Schultz, R. L. & Pease, D. C. Electron microscopy of the vascular bed of rat cerebral cortex. Am. J. Anat. 100, 409-433 (1957).
175. Simard, M., Arcuino, G., Takano, T, Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254-9262 (2003).
176. Pellerin, L. & Magistretti, P. J. Food for thought: challenging the dogmas. J. Cereb. Flow Metab. 23, 1282-1286 (2003). This paper articulates some of the issues surrounding the controversy on the role of astrocytes in neuronal energy metabolism.
177. Newman, E. A. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 26, 536-542 (2003). A lucid appraisal of the evidence that astrocytes are involved in synaptic signalling.
178. Edvinsson, L. & Hamel, E. in Cerebral Blood Flow and Metabolism (eds Edvinsson, L. & Krause, D. N.) 43-67 (Lippincott, Williams and Wilkins, Philadelphia, 2002).
179. Hachinski, V. C., Lassen, N. A. & Marshall, J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 2, 207-210 (1974).
180. Iadecola, C. & Gorelick, P. B. Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke 34, 335-337 (2003).
181. Smith, A. J. et al. Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI. Proc. Natl Acad. Sci. USA 99, 10765-10770 (2002).
182. Rees, G., Friston, K. & Koch, C. A direct quantitative relationship between the functional properties of human and macaque V5. Nature Neurosci. 3, 716-723 (2000).
183. Murphy, S., Rich, G., Orgren, K. I., Moore, S. A. & Faraci, F. M. Astrocyte-derived lipoxygenase product evokes endothelium-dependent relaxation of the basilar artery. J. Neurosci. Res. 38, 314-318 (1994).