Obesity-induced cerebral hypoperfusion derived from endothelial dysfunction: One of the risk factors for alzheimer’s disease

Current Alzheimer Research

Volumn 11, Issue 8, 2014, Pages 733-744

  Toda, Noboru ^a,b   Ayajiki, Kazuhide ^c   Okamura, Tomio ^b  

^a Toyama Institute for Cardiovascular Pharmacology Research   (Japan)

^b SHIGA UNIVERSITY OF MEDICAL SCIENCE   (Japan)

^c HYOGO COLLEGE OF MEDICINE   (Japan)

Author keywords

Alzheimer s disease; Cerebral blood flow; Endothelial function; Nitric oxide; Obesity; amyloid

Indexed keywords

ADIPOCYTOKINE; ANTIOXIDANT; CHOLINESTERASE INHIBITOR; ENDOTHELIN A RECEPTOR ANTAGONIST; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MISCELLANEOUS DRUGS AND AGENTS; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; ACETYLCHOLINESTERASE; NITRIC OXIDE;

ALZHEIMER DISEASE; ARTICLE; BARIATRIC SURGERY; BRAIN BLOOD FLOW; BRAIN PERFUSION; CLINICAL TRIAL (TOPIC); COGNITIVE DEFECT; DIETARY INTAKE; ENDOTHELIAL DYSFUNCTION; EXERCISE; EXPERIMENTAL ANIMAL; HUMAN; META ANALYSIS (TOPIC); NONHUMAN; OBESITY; PHYSICAL ACTIVITY; PRIORITY JOURNAL; PROPHYLAXIS; RISK FACTOR; BLOOD; BRAIN CIRCULATION; ENDOTHELIUM; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY;

ACETYLCHOLINESTERASE; ALZHEIMER DISEASE; CEREBROVASCULAR CIRCULATION; ENDOTHELIUM; HUMANS; NITRIC OXIDE; OBESITY; RISK FACTORS;

EID: 84926215196     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/156720501108140910120456     Document Type: Article

References (152)

1. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 163: 1524-1528 (2003).
2. de la Torre JC. Vascular basis of Alzheimer’s pathogenesis. Ann NY Acad Sci 977: 196-215 (2002).
3. Iadecola C. Neurovascular regulation in the normal brain and Alzheimer’s disease. Nat Rev Neurosci 5: 347-360 (2004).
4. Naderali EK, Ratcliffe SH, Dale MC. Obesity and Alzheimer’s disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen 24: 445-449 (2009).
5. Kalaria RN. The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging 21: 321-330 (2000).
6. de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 3: 184-190 (2004).
7. Toda N, Okamura T. Cerebral blood flow regulation by nitric oxide in Alzheimer’s disease. J Alzheimers Dis 32: 569-578 (2012).
8. Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide in neurological disorders. Can J Physiol Pharmacol 87: 581-594 (2009).
9. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Aktdependent phosphorylation. Nature 399: 601-605 (1999).
10. Toda N, Okamura T. Possible role of nitric oxide in transmitting information from vasodilator nerve to cerebroarterial muscle. Biochem Biophys Res Commun 170: 308-313 (1990).
11. Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev 55: 271-324 (2003).
12. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 62: 1556-1560 (2005).
13. Razay G, Vreugdenhil A, Wilcock G. Obesity, abdominal obesity and Alzheimer disease. Dement Geriatr Cogn Disord 22: 173-176 (2006).
14. Cournot M, Marquié JC, Ansiau D, Martinaud C, Fonds H. Ferrières J.[1] et al. Relation between body mass index and cognitive function in healthy middle-aged men and women. Neurology 67: 1208-1214 (2006).
15. Whitmer RA, Gunderson EP, Quesenberry CP, Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 4: 103-109 (2007).
16. Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obes Rev 9: 204-218 (2008).
17. Fitzpatrick AL, Kuller LH. Lopez OL, Diehr P, O’Meara ES, Longstreth WT, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 66: 336-342 (2009).
18. Qiu C. Epidemiological findings of vascular risk factors in Alzheimer’s disease: implications for therapeutic and preventive intervention. Expert Rev Neurother 11: 1593-1607 (2011).
19. Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 12: e426-e437 (2011).
20. Lee EB. Obesity, leptin and Alzheimer’s disease. Ann NY Acad Sci 1243: 15-29 (2011).
21. Kohjima M, Sun Y, Chan L. Increased food intake leads to obesity and insulin resistance in the tg2576 Alzheimer’s disease mouse model. Endocrinology 151: 1532-1540 (2010).
22. Funahashi H, Yada T, Suzuki R, Shioda S. Distribution, function, and properties of leptin receptors in the brain. Int Rev Cytol 224: 1-27 (2003).
23. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 113: 607-615 (2002).
24. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer’s A β. FASEB J 18: 1870-1878 (2004).
25. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, et al. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302: 2565-2572 (2009).
26. Niedowicz DM, Studzinski CM, Weidner AM, Platt TL, Kingry KN, Beckett TL, et al. Leptin regulates amyloid β production via the α-secretase complex. Biochim Biophys Acta 1832: 439-444 (2013).
27. Deng G, Long Y, Yu YR, Li MR. Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK-eNOS pathway. In J Obest (Lond) 34: 165-171 (2010).
28. Nishimura M, Izumiya Y, Higuchi A, Shibata R, Qiu J, Kudo C, et al. Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms. Circulation 117: 216-223 (2008).
29. Adams JD. Alzheimer’s disease, ceramide, visfatin and NAD. CNS Neurol Disord Drug Targets 7: 492-498 (2008).
30. Contreras C, Sánchez A, García-Sacristán A, Martínez MC, Andriantsitohaina R, Prieto D. Preserved insulin vasorelaxation and up-regulation of the Akt/eNOS pathway in coronary arteries from insulin resistant obese Zucker rats. Atherosclerosis 217: 331-339 (2011).
31. Grayson TH, Chadha PS, Bertrand PP, Chen H, Morris MJ, Senadheera S, et al. Increased caveolae density and caveolin-1 expression accompany impaired NO-mediated vasorelaxation in dietinduced obesity. Histochem Cell Biol 139: 309-312 (2013).
32. Andersson J, Sjöström LG, Karlsson M, Wiklund U, Hultin M, Karpe F, et al. Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women. Menopause 17: 365-371 (2010).
33. Lobato NS, Filgueira FP, Akamine EH, Davel AP, Rossoni LV, Tostes R C, et al. Obesity induced by neonatal treatment with monosodium glutamate impairs microvascular reactivity in adult rats: role of NO and prostanoids. Nutr Metab Cardiovasc Dis 21: 808-816 (2011).
34. Atochin DN, Wang A, Liu VW, Critchlow JD, Dantas AP, Looft-Wilson R, et al. The phosphorylation sate of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. J Clin Invest 117: 1961-1967 (2007).
35. Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res 66: 8-17 (1990).
36. Schwaninger RM, Sun H, Mayhan WG. Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats. Life Sci 73: 3415-3425 (2003).
37. Erdös B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C. Diabetes 53: 1352-1359 W (2004).
38. Erdös B, Snipes JA, Tulbert CD, Katakam P, Miller AW, Busja DW. Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production. Am J Physiol 290: H1264-H1270 (2006).
39. Lynch CM, Kinzenbaw DA, Chen X, Zhan S, Mezzetti E, Filosa J, et al. Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke 44: 3195-3201 (2013).
40. Mayanagi K, Katakam PV, Gáspár T, Domoki F, Busija DW. Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia. J Cereb Blood Flow Metabol 28: 1927-1935 (2008).
41. McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB. Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab 30: 267-272 (2010).
42. Val-Laillet D, Layec S, Guénin S, Meurice P, Malbert CH. Changes in brain activity after a diet-induced obesity. Obesity (Silver Spring) 19: 749-756 (2011).
43. Katakam PV, Domoki JA, Snipes JA, Busija AR, Jarajapu YP, Busija DW. Impaired mitochondria-dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance. Am J Physiol 296: R289-R298 (2009).
44. Budinger TF. Progenitor endothelial cell involvement in Alzheimer’s disease. Neurol Res 25: 617-624 (2003).
45. Kurth T, Gaziano JM, Rexrode KM, Kase CS, Cook NR, Manson JE, et al. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation 111: 1992-1998 (2005).
46. Selim M, Jones R, Novak O, Zhao P, Novak V. The effects of body mass index on cerebral blood flow velocity. Clin Auton Res 18: 331-338 (2008).
47. Wilson PW, Bozeman SR, Burton TM, Hoaglin DC, Ben-Joseph R, Pashos CL. Prediction of first events of coronary heart disease and stroke with consideration of adiposity. Circulation 118: 124-130 (2008).
48. Willeumier KC, Taylor DV, Amen DG. Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults. Obesity (Silver Spring) 19: 1095-1097 (2011).
49. Alosco ML, Spitznagel MB. Raz N, Cohen R, Sweet LH, Colbert LH, et al. Obesity interacts with cerebral hypoperfusion to exacerbate cognitive impairment in older adults with heart failure. Cerebrovasc Dis Extra 2: 88-98 (2012).
50. Falkstedt D, Hemmingsson T, Rasmussen F, Lundberg I. Body mass index in late adolescence and its association with coronary heart disease and stroke in middle age among Swedish men. Int J Obes (Lond.) 31: 777-783 (2007).
51. Montero D, Walther G, Perez-Martin A, Roche E, Vinet A. Endothelial dysfunction, inflammation, and oxidative stress in obese children and adolescents: markers and effect of lifestyle intervention. Obes Rev 13: 441-455 (2012).
52. Romero-Corral A, Sert-Kuniyoshi FH, Sierra-Johnson J, Orban M, Gami A, Davison D, et al. Modest visceral fat gain causes endothelial dysfunction in healthy humans. J Am Coll Cardiol 56: 662-666 (2010).
53. Georgescu A, Popov D, Constantin A, Nemecz M, Alexandru N, Cochoior D, et al. Dysfunction of human subcutaneous fat arterioles in obesity alone or obesity associated with Type 2 diabetes. Clin Sci (Lond.) 120: 463-472 (2011).
54. Karhunen LJ, Lappalainen RI, Vanninen EJ, Kuikka JT, Uusitupa MI. Serum leptin and regional cerebral blood flow during exposure to food in obese and normal-weight women. Neuroendocrinology 69: 154-159 (1999).
55. Beltowski J. Leptin and atherosclerosis. Atherosclerosis 189: 47-60 (2006).
56. Kwon HM, Kim BJ, Lee SH, Choi SH, Oh BH, Yoon BW. Metabolic syndrome as an independent risk factor of silent brain infarction in healthy people. Stroke 37: 466-470 (2006).
57. Li FY, Cheng KK, Lam KS, Vanhoutte PM, Xu A. Cross-talk between adipose tissue and vasculature: role of adiponectin. Acta Physiol (Oxf) 203: 167-180 (2011).
58. Nacci C, Leo V, De Benedictis L, Carratù MR, Bartolomeo N, Altomare M, et al. Elevated endothelin-1 (ET-1) levels may contribute to hypoadiponectinemia in childhood obesity. J Clin Endocrinol Metab 98: E683-E693 (2013).
59. Zhang P, Huang Y, Li Y, Shi P, Lu M, Detrano R, et al. Gender and risk factor dependence of cerebral blood flow velocity in Chinese adults. Brain Res Bull 69: 282-287 (2006).
60. de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33: 1152-1162 (2002).
61. Binnewijzend MA, Kuijer JP, Benedictus MR, van der Flier WM, Wink AM, Wattjes MP, et al. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity. Radiology 267: 221-230 (2013).
62. Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, et al. Cerebral blood flow in Alzheimer’s disease. Vasc Health Risk Manag 8: 599-611 (2012).
63. McCarty MF. Up-regulation of endothelial nitric oxide activity as a central strategy for prevention of ischemic stroke just say NO to stroke! Med Hypotheses 55: 386-403 (2000).
64. Algotsson A, Nordberg A, Almkvist O, Winblad B. Skin vessel reactivity is impaired in Alzheimer’s disease. Neurobiol Aging 16: 577(1995).
65. Borroni B, Volpi R, Martin G. Del Bono R, Archetti S, Colciaghi F, et al. Peripheral blood abnormalities in Alzheimer disease: evidence for early endothelial dysfunction. Alzheimer Dis Assoc Disord 16: 150-155 (2002).
66. Dede DS, Yavuz B, Yavuz BB, Cankurtaran M, Halil M, Ulger Z, et al. Assessment of endothelial function in Alzheimer’s disease: is Alzheimer’s disease a vascular disease? J. Am Geriatr Soc 55: 1613-1617 (2007).
67. Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer’s disease. Neurobiol Aging 24: 903-907 (2003).
68. Carlsson CM, Xu G, Wen Z, Barnet JH, Blazel HM, Chappell RJ, et al. Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer’s disease: a pilot study. Curr Arzheimer Res 9: 990-997 (2012).
69. Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci doi:10.1093/Gerona/glt177 (2013)
70. Birdsill AC, Carlsson CM, Whillette AA, Okonkwo OC, Johnson SC, Xu G, et al. Low cerebral blood flow is associated with lower memory function in metabolic syndrome. Obesity (Silver Spring) 21: 1313-1320 (2013).
71. Osmond JM, Mintz JD, Dalton B, Stepp DW. Obesity increases blood pressure, cerebral vascular remodeling, and severity of stroke in the Zucker rat. Hypertension 53: 381-386 (2009).
72. de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after chronic brain hypoperfusion: spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab 25: 663-672 (2005).
73. de la Torre JC. Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol 2012: 367516, doi: 10.1155/2012/367516 (2012).
74. Elali A, Thériault P, Préfontaine P, Rivest S. Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral β amyloid brain entry and aggregation. Acta Neuropathol Commun 1: 75 (2013).
75. Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35(14): 888-94 (2014).
76. Kuznetsova E, Schliebs R. β-Amyloid, cholinergic transmission, and cerebrovascular system a developmental study in a mouse model of Alzheimer’s disease. Curr Pharm Des 19: 6749-6765 (2013).
77. Price JM, Hellermann A, Hellermann G, Sutton ET. Aging enhances vascular dysfunction induced by the Alzheimer’s peptide β-amyloid. Neurol Res 26: 305-311 (2004).
78. Chisari M, Merlo S, Sortino MA, Salomone S. Long-term incubation with [1]-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery. Pharmacol Res 61:157-161 (2010).
79. Austin SA, Santhanam AV, Katusic ZS. Endothelial nitric oxide modulates expression and processing of amyloid precursor protein. Circ Res 107: 1498-1502 (2010).
80. Grinberg LT, Korczyn AD, Heinsen H. Cerebral amyloid angiopathy impact on endothelium. Exp Gerontol 47: 838-842 (2012).
81. Park L, Zhou P. Koizumi K, El Jamal S, Previti ML, Van Nostrand WE, et al. Brain and circulatiting levels of Aβ1-40 differentially contribute to vasomotor dysfunction in the mouse brain. Stroke 44: 198-204 (2013).
82. Popa-Wagner A, Buga AM, Popescu B, Muresanu D. Vascular cognitive impairment, dementia, aging and energy demend. A vicious cycle. J Neural Transm Epub ahead of print. (2013).
83. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300: 1027-1037 (2008).
84. Hamer M, Chida Y. Physical activity and risk of neurodegenerative diseases: a systematic review of prospective evidence. Psychol Med 39: 3-11 (2009).
85. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino, S, Tang MX, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 302: 627-637 (2009).
86. Colcombe SJ, Erickson KI, Scalf PE, Kim JS. Prakash R, McAuley E, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 61: 1166-1170 (2006).
87. Formes K, Zhang P, Tierney N, Schaller F, Shi X. Chronic physical activity mitigates cerebral hypoperfusion during central hypovolemia in elderly humans. Am J Physiol 298: H1029-H1037 (2010).
88. Gligoroska JP, Manchevska S. The effect of physical activity on cognition
89. Brown AD, McMorris CA, Longman RS, Leigh R, Hill MD, Friedenreich CM, et al. Effects of cardiorespiratory fitness and cerebral blood flow on cognitive outcomes in older women. Neurobiol Aging 31: 2047-2057 (2010).
90. Tyndall AV, Davenport MH, Wilson BJ, Burek GM, Arsenault-Lapierre G, Haley E, et al. The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. BMC Geriatr 13: 21. doi: 10.1186/1471-2318-13-21 (2013).
91. Thomas BP, Yezhuvath US, Tseng BY, Liu P, Levine BD, Zhang R, et al. Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2. J Magn Reson Imaging 38:1177-1183 (2013).
92. Bolduc V, Thorin-Trescases N, Thorin E. Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging. Am J Physiol 305: H620-633 (2013).
93. Rhyu IJ, Bytheway JA, Kohler SJ, Lange H, Lee KJ, Boklewski J, et al. Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys. Neuroscience 167: 1239-1248 (2010).
94. Huang CX. Qiu X, Wang S, Wu H, Xia L, Li C, et al. Exerciseinduced changes of the capillaries in the cortex of middle-aged rats. Neuroscience 233: 139-145 (2013).
95. Solfrizzi V, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, D’Onofrio G, et al. Mediterranean diet in predementia and dementia syndromes. Curr Alzheimer Res 8: 520-542 (2011).
96. Martinez-Lapiscina EH, Clavero P, Toledo E, Estruch R, Salas-Salvadó J, San Julián B, et al. Mediterranean diet improves cognition: PREDIMED-NAVARRA randomized trial. J Neurol Neurosurg Psychiatry 84: 1318-25 (2013).
97. Cuevas AM, Germain AM. Diet and endothelial function. Biol Res 37: 225-230 (2004).
98. Marin C, Ramirez R, Delgado-Lista J. Yubero-Serrano EM, Perez-Martinez P, Carracedo J, et al. Mediterranean diet reduces endothelial damage and improves the regenerative capapcity of endothelium. Am J Clin Nutr 93: 267-274 (2011).
99. Rallidis LS, Lekakis J, Kolomvotsou A, Zampelas A, Vamvakou G, Efstathiou S, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr 90: 263-268 (2009).
100. Demarin V, Lisak M, Morovi S. Medeterranean diet in healthy lifestyle and prevention of stroke. Acta Clin Croat 50: 67-77 (2011).
101. Toda N. Nitric oxide and dietary factors: Part IV
102. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch. Neurol 63: 1545-1550 (2006).
103. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem 16: 129-137 (2005).
104. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 276: 40-47 (2001).
105. Pleiner J, Schaller G, Mittermayer F, Marsik C, MacAllister RJ. Kapiotis S, et al. Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion. Atherosclerosis 197: 383-391 (2008).
106. Feng Y, Wang X. Antioxidant therapeies for Alzheimer’s disease. Oxid Med Cell Longev 2012:472932. doi: 10.1155/2012/472932 (2012).
107. Heo JH, Hyon-Lee , Lee KM. The possible role of antioxidant vitamin C in Alzheimer’s disease treatment and prevention. Am.J Alzheimers Dis Other Demen 28: 120-125 (2013).
108. Hamel E, Nicolakakis N, Aboulkassim T. Ongali B, Tong XK. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer’s disease. Exp Physiol 93: 116-120 (2008).
109. Murakami K, Shimizu T. Cytoplasmic superoxide radical: a possible contributing factor to intracellular Aβ oligomerization in Alzheimer disease. Commun Integr Biol 5: 255-258 (2012).
110. Park L, Zhou P, Pitstick R, Capone C, Anrather J. Norris EH, et al. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105: 1347-1352 (2008).
111. Miller AA, Drummond GR, De Silva TM, Mast AE, Hickey H, Williams JP, et al. NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: role of Nox2. Am J Physiol 296: H220-H225 (2009).
112. Scremin OU, Allen K, Torres C, Scremin AM. Physostigmine enhances blood flow-metabolism ratio in neocortex. Neuropsychopharmacology 1: 297-303 (1988).
113. Ebmeier P, Hunter R, Curran SM, Dougal NJ, Murray CL, Wyper DJ, et al. Effects of a single dose of the acetylcholinesterase inhibitor velnacrine on recognition memory and regional blood flow in Alzheimer’s disease. Psychpharmacology (Berl) 108: 103-109 (1992).
114. Rosengarten B, Paulsen S, Molnar S, Kaschel R, Gallhofer B, Kaps M. Acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients. J Neurol 253: 58-64 (2006).
115. Shimizu S, Hanyu H, Iwamoto T, Koizumi K, Abe K. SPECT follow-up study of cerebral blood flow changes during Donepezil therapy in patients with Alzheimer’s disease. J Neuroimaging 16: 16-23 (2006).
116. Cho H, Kwon JH, Seo HJ, Kim JS. The short-term effect of acetylcholinesterase inhibitor on the regional cerebral blood flow of Alzheimer’s disease. Arch Gerontol Geriatr 50: 222-226 (2010).
117. Li W, Antuono PG, Xie C, Chen G, Jones JL, Ward BD, et al. Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer’s disease after 12-week donepezil treatment. Neuroimage 60: 1083-1091 (2012).
118. Toda N, Ayajiki K, Tanaka T, Okamura T. Preganglionic and postganglionic neurons responsible for cerebral vasodilatation mediated by nitric oxide in anesthetized dogs. J Cereb Blood Flow Metab 20: 700-708 (2000).
119. Toda N, Tanaka T, Ayajiki K, Okamura T. Cerebral vasodilatation induced by stimulation of the pterygopalatine ganglion and greater petrosal nerve in anesthetized monkeys. Neuroscience 96: 393-398 (2000).
120. Linville DG, Giacobini E, Arnerić SP. Heptyl-physostigmine enhances basal forebrain control of cortical cerebral blood flow. J Neurosci Res 31: 573-577 (1992).
121. Seylaz J, Hara H, Pinard E, Mraovitch S, Mackenzie ET, Edvinsson L. Effect of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat. J Cereb Blood Flow Metab 8: 875-878 (1988).
122. Suzuki N, Hardebo JE, Kåhrström J, Owman C. Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat. J Cereb Blood Flow Metab 10: 383-391 (1990).
123. Toda N. Relaxant responses to transmural stimulation and nicotine of dog and monkey cerebral arteries. Am J Physiol 243: H145-H153 (1982).
124. Tsujimoto S, Sakaki T, Morimoto T, Tominaga M. The effect of acetylcholinesterase inhibitor (SDZ ENA 713) for r-CBF and focal cerebral ischemia. Acta Neurochir (Wien) 124: 127-131 (1993).
125. Sadoshima S, Ibayashi S, Fujii K, Nagao T, Sugimori H, Fujishima M. Inhibition of acetylcholinesterase modulates the autoregulation of cerebral blood flow and attenuates ischemic brain metabolism in hypertensive rats. J Cereb Blood Flow Metab 15: 845-851 (1995).
126. Wolozin B, Bednar MM. Interventions for heart disease and their effects on Alzheimer’s disease. Neurol Res 28: 630-636 (2006).
127. Tong XK, Nicolakakis N, Fernandes P, Ongali B, Brouillette J, Quirion R, et al. Simvastatin improves cerebrovascular function and counters soluble amyloid-β, inflammation and oxidative stress in aged APP mice. Neurobiol Dis 35: 406-414 (2009).
128. Reiss AB, Wirkowski E. Statins in neurological disorders: mechanisms and therapeutic value. Scientific World Journal 9: 1242-1259 (2009).
129. Nicolakakis N, Hamel E. The nuclear receptor PPARα as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer’s disease. Front Aging Neurosci 2. doi: pii: 21. 10.3389/fnagi.2010.00021 (2010).
130. Ketsawatsomkron P, Pelham CJ, Groh S, Keen L, Faraci FM, Sigmund CD. Does peroxisome proliferator-activated receptor-α (PPARα) protect from hypertension directly through effects in the vasculature? J Biol Chem 285: 9311-9316 (2010).
131. Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. PPARα agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension 43: 661-666 (2004).
132. Sigmund CD. Endothelial and vascular muscle PPARα in arterial pressure regulation: lessons from genetic interference and deficiency. Hypertension 55: 437-444 (2010).
133. Calnek DS, Mazzella L, Roser S, Roman J. Hart CM. Peroxisome proliferator-activated receptor-α ligands increase release of nitric oxide from endothelial cells. Arterioscler. Thromb VascBiol 23: 52-57 (2003).
134. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-
135. Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rose-Neto P, et al. Complete rescue of cerebrovascular function in aged Alzheimer’s disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor-α agonist. J Neurosci 28: 9287-9296 (2008).
136. Nicolakakis N, Aboulkassim T, Aliaga A, Tong XK, Rose-Neto P, Hamel E. Intact memory in TGF-β1 transgemic mice featuring chronic cerebrovascular defect: recovery with pioglitazone. J Cereb Blood Flow Metab 31: 200-211 (2011).
137. Ramzy D, Rao V, Tumiati LC, Xu N, Sheshgiri R, Miriuka S, et al. Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation 114 (1 Suppl): 1319-1326 (2006).
138. Palmer J, Love S. Endothelin receptor antagonists: potential in Alzheimer’s disease. Pharmacol Res 63: 525-531 (2011).
139. Khalil Z, Poliviou H, Maynard CJ, Beyreuther K, Masters CL, Li Q. X. Mechanisms of peripheral microvascular dysfunction in transgenic mice overexpressing the Alzheimer’s disease amyloid Aβ protein. J Alzheimers Dis 4: 467-478 (2002).
140. Elesber AA, Bonetti PO, Woodrum JE, Zhu X, Lerman LO, Younkin S G, et al. Bosentan preserves endothelial function in mice overexpressing APP. Neurobiol Aging 27: 446-450 (2006).
141. Li Z, Zhao G, Qian S, Yang Z, Chen J, Cai C, et al. Cerebrovascular protection of [1]-asarone in Alzheimer’s disease rats: a behavioral, cerebral blood flow, biochemical and genic study. J Ethnopharmacol 44: 305-312 (2012).
142. Ejaz Ahmed M., Khan MM, Javed H, Vaibhav K, Khan A, Tabassum R, et al. Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocininduced experimental dementia of Alzheimer’s type. Neurochem Int 62: 492-501(2013).
143. Natarajan S, Shunmugiah KP, Kasi PD. Plants traditionally used in age-related brain disorders (dementia): an ethanopharmacological survey. Pharm Biol 51: 492-523 (2013).
144. Gokce N, Vita JA, McDonnell M, Forse AR, Istfan N, Stoeckl M, et al. Effect of medical and surgical weight loss on endothelial vasomotor function in obese patients. Am J Cardiol 95: 266-268 (2005).
145. Vázquez LA, Pazos F, Berrazueta JR, Fernández-Escalante C. García-Unzueta MT, Freijanes J, et al. Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery. J Clin Endocrinol Metab 90: 316-322 (2005).
146. Williams IL, Chowienczyk PJ, Wheatcroft SB, Patel AG, Sherwood RA, Momin A, et al. Endothelial function and weight loss in obese humans. Obes Surg 15: 1055-1060 (2005).
147. Sturm W, Tschoner A, Engl J, Kaser S, Laaimer M, Ciardi C, et al. Effect of bariatric surgery on both functional and structural measures of premature atherosclerosis. Eur Heart J 30: 2038-2043 (2009).
148. Nerla R, Tarzia P, Sestito A, Di Monaco A, Infusino F, Matera D, et al. Effect of bariatric surgery on peripheral flow-mediated dilation and coronary microvascular function. Nutr Metab Cardiovasc Dis 22: 626-634 (2012).
149. Tschoner A, Sturm W, Gelsinger C, Ress C, Laimer M, Engl J, et al. Long-term effects of pronounced weight loss after bariatric surgery on functional and structural markers of atherosclerosis. Obesity (Silver Spring), 21:1960-1965 (2013).
150. Sledzinski T. Sledzinski M, Smolenski RT, Swierczynski J. Increased serum nitric oxide concentration after bariatric surgery a potential mechanism for cardiovascular benefit. Obes Surg 20: 204-210 (2010).
151. Saleh MH, Bertolami MC, Assef JE, Taha MI, de Freitas W, Petisco A C, et al. Improvement of atherosclerotic markers in nondiabetic patients after bariatric surgery. Obes Surg 22: 1701-1707 (2012).
152. Zhang H, Wang Y, Zhang J, Potter BJ, Sowers JR, Zhang C. Bariatric surgery reduces visceral adipose inflammation and improves endothelial function in type 2 diabetic mice. Arterioscler Thromb Vasc Biol 31: 2063-2069 (2011).