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Cognitive Dysfunction and Dementia in Animal Models of Hypertension

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Hypertension and the Brain as an End-Organ Target

Abstract

Since decades, epidemiological data have shown a high prevalence of hypertension (HT) in vascular dementia (VaD) and Alzheimer’s disease (AD). However, while antihypertensive treatments show a clear protective effect against stroke-related cognitive impairments, their beneficial effects against mild cognitive impairment (MCI) or other forms of dementia remain to be clearly established. Structural and functional vascular alterations in the brain are exposing the need for new experiments with validated animal models of HT in order to better understand the biological links between HT, cognitive impairment, and dementia.

While most publications on dementia have focused on AD mouse models, a recent interest has emerged for a better understanding of the association between vascular diseases and cognition. Therefore, this chapter focuses on published data in animal models of HT related to cognitive dysfunction. The first part will present models of genetic HT such as spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats (DS)‚ and of HT induced by Angiotensin II (Ang II) and by transverse aortic constriction (TAC) in the context of cognitive functions. In the second part, we will discuss the consequences of HT on cerebrovascular function. Finally, we will review the potential benefits of antihypertensive drugs acting on the renin–angiotensin system (RAS) on cognitive deficits.

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References

  1. Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963;27:282–93.

    Article  CAS  PubMed  Google Scholar 

  2. Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev. 1999;79(4):1227–82.

    CAS  PubMed  Google Scholar 

  3. De Bruin NM, et al. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003;80(1):63–79.

    Article  PubMed  CAS  Google Scholar 

  4. Sabbatini M, et al. The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mech Ageing Dev. 2002;123(5):547–59.

    Article  CAS  PubMed  Google Scholar 

  5. Sabbatini M, et al. Effect of nicardipine treatment on the expression of neurofilament 200 KDa immunoreactivity in the brain of spontaneously hypertensive rats. Clin Exp Hypertens. 2001;23(1–2):127–41.

    Article  CAS  PubMed  Google Scholar 

  6. Sabbatini M, et al. The hippocampus in spontaneously hypertensive rats: a quantitative microanatomical study. Neuroscience. 2000;100(2):251–8.

    Article  CAS  PubMed  Google Scholar 

  7. Kozuka M, et al. Effects of S-adenosyl-L-methionine upon ischemia-induced brain edema in Mongolian gerbils and spontaneously hypertensive rats. Jpn J Pharmacol. 1988;46(3):225–36.

    Article  CAS  PubMed  Google Scholar 

  8. Skarphedinsson JO, et al. Relative cerebral ischemia in SHR due to hypotensive hemorrhage: cerebral function, blood flow and extracellular levels of lactate and purine catabolites. J Cereb Blood Flow Metab. 1989;9(3):364–72.

    Article  CAS  PubMed  Google Scholar 

  9. van der Staay FJ, Augstein KH, Horvath E. Sensorimotor impairments in rats with cerebral infarction, induced by unilateral occlusion of the left middle cerebral artery: strain differences and effects of the occlusion site. Brain Res. 1996;735(2):271–84.

    Article  PubMed  Google Scholar 

  10. Sabbatini M, et al. Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovascular disease of the elderly. Mech Ageing Dev. 2001;122(12):1257–68.

    Article  CAS  PubMed  Google Scholar 

  11. Meneses A, Hong E. Spontaneously hypertensive rats: a potential model to identify drugs for treatment of learning disorders. Hypertension. 1998;31(4):968–72.

    Article  CAS  PubMed  Google Scholar 

  12. Hecht K, et al. Learning and memory processes during postnatal ontogenesis in rats with spontaneous hypertension. Acta Biol Med Ger. 1978;37(9):1471–8.

    CAS  PubMed  Google Scholar 

  13. Wyss JM, Fisk G, van Groen T. Impaired learning and memory in mature spontaneously hypertensive rats. Brain Res. 1992;592(1–2):135–40.

    Article  CAS  PubMed  Google Scholar 

  14. Clough DP, et al. Hypotensive action of captopril in spontaneously hypertensive and normotensive rats. Interference with neurogenic vasoconstriction. Hypertension. 1982;4(6):764–72.

    Article  CAS  PubMed  Google Scholar 

  15. Widy-Tyszkiewicz E, Scheel-Kruger J, Christensen AV. Spatial navigation learning in spontaneously hypertensive, renal hypertensive and normotensive Wistar rats. Behav Brain Res. 1993;54(2):179–85.

    Article  CAS  PubMed  Google Scholar 

  16. Knardahl S, Sagvolden T. Two-way active avoidance behavior of spontaneously hypertensive rats: effect of intensity of discontinuous shock. Behav Neural Biol. 1982;35(2):105–20.

    Article  CAS  PubMed  Google Scholar 

  17. Knardahl S, Karlsen K. Passive-avoidance behavior of spontaneously hypertensive rats. Behav Neural Biol. 1984;42(1):9–22.

    Article  CAS  PubMed  Google Scholar 

  18. Low WC, Whitehorn D, Hendley ED. Genetically related rats with differences in Hippocampal uptake of norepinephrine and maze performance. Brain Res Bull. 1984;12(6):703–9.

    Article  CAS  PubMed  Google Scholar 

  19. Whitehorn D, et al. Independence of blood pressure and locomotor hyperactivity in normotensive and genetically hypertensive rat. Behav Neural Biol. 1983;37(2):357–61.

    Article  CAS  PubMed  Google Scholar 

  20. Sagvolden T, Hendley ED, Knardahl S. Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined. Physiol Behav. 1992;52(1):49–57.

    Article  CAS  PubMed  Google Scholar 

  21. Sagvolden T, Sergeant JA. Attention deficit/hyperactivity disorder—from brain dysfunctions to behaviour. Behav Brain Res. 1998;94(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  22. Wultz B, et al. The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Neural Biol. 1990;53(1):88–102.

    Article  CAS  PubMed  Google Scholar 

  23. Svensson L, Harthon C, Linder B. Evidence for a dissociation between cardiovascular and behavioral reactivity in the spontaneously hypertensive rat. Physiol Behav. 1991;49(4):661–5.

    Article  CAS  PubMed  Google Scholar 

  24. Soderpalm B. The SHR exhibits less “anxiety” but increased sensitivity to the anticonflict effect of clonidine compared to normotensive controls. Pharmacol Toxicol. 1989;65(5):381–6.

    Article  CAS  PubMed  Google Scholar 

  25. Turkkan JS. Behavioral performance effects of antihypertensive drugs: human and animal studies. Neurosci Biobehav Rev. 1988;12(2):111–22.

    Article  CAS  PubMed  Google Scholar 

  26. Wyss JM, et al. Age-related decline in water maze learning and memory in rats: strain differences. Neurobiol Aging. 2000;21(5):671–81.

    Article  CAS  PubMed  Google Scholar 

  27. Dahl LK, Heine M, Tassinari L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Nature. 1962;194:480–2.

    Article  CAS  PubMed  Google Scholar 

  28. Campese VM. Salt sensitivity in hypertension. Renal and cardiovascular implications. Hypertension. 1994;23(4):531–50.

    Article  CAS  PubMed  Google Scholar 

  29. Terry Jr AV, Hernandez CM, Buccafusco JJ. Dahl salt-sensitive and salt-resistant rats: examination of learning and memory performance, blood pressure, and the expression of central nicotinic acetylcholine receptors. Neuroscience. 2001;103(2):351–63.

    Article  CAS  PubMed  Google Scholar 

  30. Ruiz-Opazo N, Lopez LV, Tonkiss J. Modulation of learning and memory in Dahl rats by dietary salt restriction. Hypertension. 2004;43(4):797–802.

    Article  CAS  PubMed  Google Scholar 

  31. Pelisch N, et al. Blockade of AT1 receptors protects the blood-brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats. Am J Hypertens. 2011;24(3):362–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hirawa N, et al. Long-term inhibition of renin-angiotensin system sustains memory function in aged Dahl rats. Hypertension. 1999;34(3):496–502.

    Article  CAS  PubMed  Google Scholar 

  33. Amouyel P, et al. The renin angiotensin system and Alzheimer’s disease. Ann N Y Acad Sci. 2000;903:437–41.

    Article  CAS  PubMed  Google Scholar 

  34. McKinley MJ, et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol. 2003;35(6):901–18.

    Article  CAS  PubMed  Google Scholar 

  35. Lautner RQ, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11.

    Article  CAS  PubMed  Google Scholar 

  36. Bloch S, Obari D, Girouard H. Angiotensin and neurovascular coupling: beyond hypertension. Microcirculation. 2015;22(3):159–67.

    CAS  PubMed  Google Scholar 

  37. Capone C, et al. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am J Physiol Heart Circ Physiol. 2011;300(1):H397–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reinecke K, et al. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J. 2003;17(14):2094–6.

    CAS  PubMed  Google Scholar 

  39. Inaba S, et al. Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension. 2009;53(2):356–62.

    Article  CAS  PubMed  Google Scholar 

  40. Carey RM. Newly discovered components and actions of the renin-angiotensin system. Hypertension. 2013;62(5):818–22.

    Article  CAS  PubMed  Google Scholar 

  41. Gard PR. The role of angiotensin II in cognition and behaviour. Eur J Pharmacol. 2002;438(1-2):1–14.

    Article  CAS  PubMed  Google Scholar 

  42. de Gasparo M, et al. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52(3):415–72.

    PubMed  Google Scholar 

  43. Jankowski V, et al. Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects. FASEB J. 2011;25(9):2987–95.

    Article  CAS  PubMed  Google Scholar 

  44. van Esch JH, et al. Effects of angiotensin II and its metabolites in the rat coronary vascular bed: is angiotensin III the preferred ligand of the angiotensin AT2 receptor? Eur J Pharmacol. 2008;588(2–3):286–93.

    Article  PubMed  CAS  Google Scholar 

  45. Swanson GN, et al. Discovery of a distinct binding site for angiotensin II (3-8), a putative angiotensin IV receptor. Regul Pept. 1992;40(3):409–19.

    Article  CAS  PubMed  Google Scholar 

  46. Georgiev V, Yonkov D. Participation of angiotensin II in learning and memory. I. Interaction of angiotensin II with saralasin. Methods Find Exp Clin Pharmacol. 1985;7(8):415–8.

    CAS  PubMed  Google Scholar 

  47. Karwowska-Polecka W, et al. Losartan influences behavioural effects of angiotensin II(3-7) in rats. Pharmacol Res. 1997;36(4):275–83.

    Article  CAS  PubMed  Google Scholar 

  48. Morgan JM, Routtenberg A. Angiotensin injected into the neostriatum after learning disrupts retention performance. Science. 1977;196(4285):87–9.

    Article  CAS  PubMed  Google Scholar 

  49. Lee EH, et al. Impaired retention by angiotensin II mediated by the AT1 receptor. Peptides. 1995;16(6):1069–71.

    Article  CAS  PubMed  Google Scholar 

  50. Picard P, Chretien L, Couture R. Functional interaction between losartan and central tachykinin NK3 receptors in the conscious rat. Br J Pharmacol. 1995;114(8):1563–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Duchemin S, et al. Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice. Physiol Behav. 2013;109:63–8.

    Article  CAS  PubMed  Google Scholar 

  52. Rockman HA, et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci U S A. 1991;88(18):8277–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Poulet R, et al. Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab. 2006;26(2):253–62.

    Article  CAS  PubMed  Google Scholar 

  54. Li YH, et al. Remodeling of carotid arteries is associated with increased expression of thrombomodulin in a mouse transverse aortic constriction model. Thromb Haemost. 2007;97(4):658–64.

    CAS  PubMed  Google Scholar 

  55. Phinney AL, et al. In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A. 2003;100(24):14193–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Carnevale D, et al. Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012;60(1):188–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Deane R, et al. A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012;122(4):1377–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sharp SI, et al. Hypertension is a potential risk factor for vascular dementia: systematic review. Int J Geriatr Psychiatry. 2011;26(7):661–9.

    Article  PubMed  Google Scholar 

  59. Skoog I, Gustafson D. Update on hypertension and Alzheimer’s disease. Neurol Res. 2006;28(6):605–11.

    Article  PubMed  Google Scholar 

  60. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet. 1974;2(7874):207–10.

    Article  CAS  PubMed  Google Scholar 

  61. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci. 1970;11(3):205–42.

    Article  CAS  PubMed  Google Scholar 

  62. O’Brien JT, et al. Cognitive associations of subcortical white matter lesions in older people. Ann N Y Acad Sci. 2002;977:436–44.

    Article  PubMed  Google Scholar 

  63. Gorelick PB, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2011;42(9):2672–713.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Ransmayr G. Difficulties in the clinical diagnosis of vascular dementia and dementia of the Alzheimer type—comparison of clinical classifications. J Neural Transm Suppl. 1998;53:79–90.

    Article  CAS  PubMed  Google Scholar 

  65. Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80(4):844–66.

    Article  CAS  PubMed  Google Scholar 

  66. Wiesmann M, Kiliaan AJ, Claassen JA. Vascular aspects of cognitive impairment and dementia. J Cereb Blood Flow Metab. 2013;33(11):1696–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. O’Brien JT, et al. Vascular cognitive impairment. Lancet Neurol. 2003;2(2):89–98.

    Article  PubMed  Google Scholar 

  68. Snowdon DA, et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813–7.

    Article  CAS  PubMed  Google Scholar 

  69. Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7(6):476–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5(5):347–60.

    Article  CAS  PubMed  Google Scholar 

  71. de la Torre JC. Vascular risk factor detection and control may prevent Alzheimer’s disease. Ageing Res Rev. 2010;9(3):218–25.

    Article  PubMed  CAS  Google Scholar 

  72. Jellinger KA. Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. Neurodegener Dis. 2010;7(1-3):112–5.

    Article  CAS  PubMed  Google Scholar 

  73. Kalaria RN. Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr Rev. 2010;68 Suppl 2:S74–87.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci. 2008;9(3):169–81.

    Article  CAS  PubMed  Google Scholar 

  75. Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid, and hypertension. Stroke. 2009;40(3 Suppl):S40–4.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201.

    Article  CAS  PubMed  Google Scholar 

  77. Ritter S, Dinh TT. Progressive postnatal dilation of brain ventricles in spontaneously hypertensive rats. Brain Res. 1986;370(2):327–32.

    Article  CAS  PubMed  Google Scholar 

  78. Tajima A, et al. Smaller local brain volumes and cerebral atrophy in spontaneously hypertensive rats. Hypertension. 1993;21(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  79. Nelson DO, Boulant JA. Altered CNS neuroanatomical organization of spontaneously hypertensive (SHR) rats. Brain Res. 1981;226(1-2):119–30.

    Article  CAS  PubMed  Google Scholar 

  80. Sabbatini M, Tomassoni D, Amenta F. Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats. Mech Ageing Dev. 2001;122(16):2085–105.

    Article  CAS  PubMed  Google Scholar 

  81. Bendel P, Eilam R. Quantitation of ventricular size in normal and spontaneously hypertensive rats by magnetic resonance imaging. Brain Res. 1992;574(1-2):224–8.

    Article  CAS  PubMed  Google Scholar 

  82. Pantoni L, Garcia JH. Cognitive impairment and cellular/vascular changes in the cerebral white matter. Ann N Y Acad Sci. 1997;826:92–102.

    Article  CAS  PubMed  Google Scholar 

  83. Englund E. Neuropathology of white matter changes in Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord. 1998;9 Suppl 1:6–12.

    Article  PubMed  Google Scholar 

  84. Schmidt R, et al. Cognitive impairment after acute supratentorial stroke: a 6-month follow-up clinical and computed tomographic study. Eur Arch Psychiatry Clin Neurosci. 1993;243(1):11–5.

    Article  CAS  PubMed  Google Scholar 

  85. Fredriksson K, Nordborg C, Johansson BB. The hemodynamic effect of bilateral carotid artery ligation and the morphometry of the main communicating circuit in normotensive and spontaneously hypertensive rats. Acta Physiol Scand. 1984;121(3):241–7.

    Article  CAS  PubMed  Google Scholar 

  86. Johansson BB, Fredriksson K. Cerebral arteries in hypertension: structural and hemodynamic aspects. J Cardiovasc Pharmacol. 1985;7 Suppl 2:S90–3.

    Article  PubMed  Google Scholar 

  87. Heagerty AM, et al. Small artery structure in hypertension. Dual processes of remodeling and growth. Hypertension. 1993;21(4):391–7.

    Article  CAS  PubMed  Google Scholar 

  88. Mulvany MJ. Resistance vessel structure and the pathogenesis of hypertension. J Hypertens Suppl. 1993;11(5):S7–12.

    Article  CAS  PubMed  Google Scholar 

  89. Kivipelto M, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ. 2001;322(7300):1447–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–13.

    Article  PubMed  Google Scholar 

  91. Gentile MT, et al. Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009;30(2):222–8.

    Article  CAS  PubMed  Google Scholar 

  92. Faraco G, et al. Hypertension enhances Abeta-induced neurovascular dysfunction, promotes beta-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab. 2015;7:115. doi:10.1038/jcbfm.2015.79.

    Google Scholar 

  93. Ando H, et al. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke. 2004;35(7):1726–31.

    Article  CAS  PubMed  Google Scholar 

  94. Saavedra JM, Nishimura Y. Angiotensin and cerebral blood flow. Cell Mol Neurobiol. 1999;19(5):553–73.

    Article  CAS  PubMed  Google Scholar 

  95. Didion SP, Sigmund CD, Faraci FM. Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen. Stroke. 2000;31(3):760–4. discussion 765.

    Article  CAS  PubMed  Google Scholar 

  96. Baumbach GL, Sigmund CD, Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension. 2003;41(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  97. Kazama K, et al. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol. 2003;285(5):H1890–9.

    Article  CAS  PubMed  Google Scholar 

  98. Kazama K, et al. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res. 2004;95(10):1019–26.

    Article  CAS  PubMed  Google Scholar 

  99. Girouard H, et al. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2007;27(2):303–9.

    Article  CAS  PubMed  Google Scholar 

  100. Girouard H, et al. The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic. Am J Physiol Heart Circ Physiol. 2008;294(1):H156–63.

    Article  CAS  PubMed  Google Scholar 

  101. Girouard H, et al. Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through nox-2-derived radicals. Arterioscler Thromb Vasc Biol. 2006;26(4):826–32.

    Article  CAS  PubMed  Google Scholar 

  102. Capone C, et al. Estrous cycle-dependent neurovascular dysfunction induced by angiotensin II in the mouse neocortex. Hypertension. 2009;54(2):302–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Capone C, et al. Cyclooxygenase 1-derived prostaglandin E2 and EP1 receptors are required for the cerebrovascular dysfunction induced by angiotensin II. Hypertension. 2010;55(4):911–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lipsitz LA, et al. Antihypertensive therapy increases cerebral blood flow and carotid distensibility in hypertensive elderly subjects. Hypertension. 2005;45(2):216–21.

    Article  CAS  PubMed  Google Scholar 

  105. Efimova IY, et al. Brain perfusion and cognitive function changes in hypertensive patients. Hypertens Res. 2008;31(4):673–8.

    Article  PubMed  Google Scholar 

  106. Oku N, et al. Hemodynamic influences of losartan on the brain in hypertensive patients. Hypertens Res. 2005;28(1):43–9.

    Article  CAS  PubMed  Google Scholar 

  107. Kimura Y, et al. Blood pressure lowering with valsartan is associated with maintenance of cerebral blood flow and cerebral perfusion reserve in hypertensive patients with cerebral small vessel disease. J Stroke Cerebrovasc Dis. 2010;19(2):85–91.

    Article  PubMed  Google Scholar 

  108. Nagata R, Kawabe K, Ikeda K. Olmesartan, an angiotensin II receptor blocker, restores cerebral hypoperfusion in elderly patients with hypertension. J Stroke Cerebrovasc Dis. 2010;19(3):236–40.

    Article  PubMed  Google Scholar 

  109. Muller M, et al. Hypertension and longitudinal changes in cerebral blood flow: the SMART-MR study. Ann Neurol. 2012;71(6):825–33.

    Article  PubMed  Google Scholar 

  110. Vital SA, et al. Mechanisms underlying the cerebral microvascular responses to angiotensin II-induced hypertension. Microcirculation. 2010;17(8):641–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang M, et al. Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience. 2010;171(3):852–8.

    Article  CAS  PubMed  Google Scholar 

  112. Zlokovic BV. Clearing amyloid through the blood-brain barrier. J Neurochem. 2004;89(4):807–11.

    Article  CAS  PubMed  Google Scholar 

  113. Yan SD, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature. 1996;382(6593):685–91.

    Article  CAS  PubMed  Google Scholar 

  114. Donahue JE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol. 2006;112(4):405–15.

    Article  CAS  PubMed  Google Scholar 

  115. Arancio O, et al. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 2004;23(20):4096–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Deane R, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–13.

    Article  CAS  PubMed  Google Scholar 

  117. Willnow TE, et al. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci U S A. 1995;92(10):4537–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Van Uden E, et al. Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer’s disease pathogenesis? Mol Cell Neurosci. 1999;14(2):129–40.

    Article  PubMed  Google Scholar 

  119. Veinbergs I, et al. Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E. Exp Neurol. 2001;170(1):15–26.

    Article  CAS  PubMed  Google Scholar 

  120. Van Uden E, et al. Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci. 2002;22(21):9298–304.

    PubMed  Google Scholar 

  121. Barry DI. Cerebral blood flow in hypertension. J Cardiovasc Pharmacol. 1985;7 Suppl 2:S94–8.

    Article  PubMed  Google Scholar 

  122. Mentis MJ, et al. Reduction of functional neuronal connectivity in long-term treated hypertension. Stroke. 1994;25(3):601–7.

    Article  CAS  PubMed  Google Scholar 

  123. Park L, et al. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab. 2007;27(12):1908–18.

    Article  CAS  PubMed  Google Scholar 

  124. Beason-Held LL, et al. Longitudinal changes in cerebral blood flow in the older hypertensive brain. Stroke. 2007;38(6):1766–73.

    Article  PubMed  Google Scholar 

  125. Passingham D, Sakai K. The prefrontal cortex and working memory: physiology and brain imaging. Curr Opin Neurobiol. 2004;14(2):163–8.

    Article  PubMed  CAS  Google Scholar 

  126. Gilboa A. Autobiographical and episodic memory—one and the same? Evidence from prefrontal activation in neuroimaging studies. Neuropsychologia. 2004;42(10):1336–49.

    Article  PubMed  Google Scholar 

  127. Eslinger PJ, Flaherty-Craig CV, Benton AL. Developmental outcomes after early prefrontal cortex damage. Brain Cogn. 2004;55(1):84–103.

    Article  PubMed  Google Scholar 

  128. Ullsperger M, von Cramon DY. Subprocesses of performance monitoring: a dissociation of error processing and response competition revealed by event-related fMRI and ERPs. Neuroimage. 2001;14(6):1387–401.

    Article  CAS  PubMed  Google Scholar 

  129. Courtney SM, et al. Object and spatial visual working memory activate separate neural systems in human cortex. Cereb Cortex. 1996;6(1):39–49.

    Article  CAS  PubMed  Google Scholar 

  130. Grady CL, et al. Dissociation of object and spatial vision in human extrastriate cortex: age-related changes in activation of regional cerebral blood flow measured with [(15) o]water and positron emission tomography. J Cogn Neurosci. 1992;4(1):23–34.

    Article  CAS  PubMed  Google Scholar 

  131. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124(3):319–35.

    Article  CAS  PubMed  Google Scholar 

  132. Eriksson PS, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7.

    Article  CAS  PubMed  Google Scholar 

  133. Cameron HA, et al. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56(2):337–44.

    Article  CAS  PubMed  Google Scholar 

  134. Seki T, Arai Y. Highly polysialylated neural cell adhesion molecule (NCAM-H) is expressed by newly generated granule cells in the dentate gyrus of the adult rat. J Neurosci. 1993;13(6):2351–8.

    CAS  PubMed  Google Scholar 

  135. McNamara RK, Skelton RW. The neuropharmacological and neurochemical basis of place learning in the Morris water maze. Brain Res Brain Res Rev. 1993;18(1):33–49.

    Article  CAS  PubMed  Google Scholar 

  136. Aimone JB, Wiles J, Gage FH. Computational influence of adult neurogenesis on memory encoding. Neuron. 2009;61(2):187–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kitamura T, et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009;139(4):814–27.

    Article  CAS  PubMed  Google Scholar 

  138. Akers KG, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344(6184):598–602.

    Article  CAS  PubMed  Google Scholar 

  139. Togashi H, et al. Effects of clonidine and guanfacine on drinking and ambulation in spontaneously hypertensive rats. Pharmacol Biochem Behav. 1982;17(3):519–22.

    Article  CAS  PubMed  Google Scholar 

  140. Sanchez F, et al. Dendritic morphology of neurons in medial prefrontal cortex, hippocampus, and nucleus accumbens in adult SH rats. Synapse. 2011;65(3):198–206.

    Article  CAS  PubMed  Google Scholar 

  141. Kronenberg G, Lippoldt A, Kempermann G. Two genetic rat models of arterial hypertension show different mechanisms by which adult hippocampal neurogenesis is increased. Dev Neurosci. 2007;29(1-2):124–33.

    Article  CAS  PubMed  Google Scholar 

  142. Hanon O, et al. Prevention of dementia and cerebroprotection with antihypertensive drugs. Curr Hypertens Rep. 2004;6(3):201–7.

    Article  PubMed  Google Scholar 

  143. Kehoe PG, Miners S, Love S. Angiotensins in Alzheimer’s disease—friend or foe? Trends Neurosci. 2009;32(12):619–28.

    Article  CAS  PubMed  Google Scholar 

  144. Croog SH, et al. The effects of antihypertensive therapy on the quality of life. N Engl J Med. 1986;314(26):1657–64.

    Article  CAS  PubMed  Google Scholar 

  145. Rozzini L, et al. Angiotensin converting enzyme (ACE) inhibitors modulate the rate of progression of amnestic mild cognitive impairment. Int J Geriatr Psychiatry. 2006;21(6):550–5.

    Article  PubMed  Google Scholar 

  146. Yasar S, et al. The use of angiotensin-converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women. Clin Pharmacol Ther. 2008;84(1):119–26.

    Article  CAS  PubMed  Google Scholar 

  147. Li NC, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Davies NM, et al. Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimers Dis. 2011;26(4):699–708.

    PubMed  Google Scholar 

  149. Hu J, et al. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001;276(51):47863–8.

    CAS  PubMed  Google Scholar 

  150. Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280(45):37644–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Toropygin IY, et al. The N-domain of angiotensin-converting enzyme specifically hydrolyzes the Arg-5-His-6 bond of Alzheimer’s Abeta-(1-16) peptide and its isoAsp-7 analogue with different efficiency as evidenced by quantitative matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 2008;22(2):231–9.

    Article  CAS  PubMed  Google Scholar 

  152. Yamada K, et al. Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer’s disease. Brain Res. 2010;1352:176–86.

    Article  CAS  PubMed  Google Scholar 

  153. Dong YF, et al. Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer’s disease. FASEB J. 2011;25(9):2911–20.

    Article  CAS  PubMed  Google Scholar 

  154. Miners JS, et al. Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer’s disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol. 2008;34(2):181–93.

    Article  CAS  PubMed  Google Scholar 

  155. Hou DR, et al. Altered angiotensin-converting enzyme and its effects on the brain in a rat model of Alzheimer disease. Chin Med J (Engl). 2008;121(22):2320–3.

    CAS  Google Scholar 

  156. AbdAlla S, et al. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer’s disease. Int J Mol Sci. 2013;14(8):16917–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Zou K, et al. Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition. J Neurosci. 2007;27(32):8628–35.

    Article  CAS  PubMed  Google Scholar 

  158. Ohrui T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology. 2004;63(7):1324–5.

    Article  CAS  PubMed  Google Scholar 

  159. Sink KM, et al. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med. 2009;169(13):1195–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tzourio C. Vascular factors and cognition: toward a prevention of dementia? J Hypertens Suppl. 2003;21(5):S15–9.

    Article  CAS  PubMed  Google Scholar 

  161. Yamada K, et al. Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats. Brain Res. 2011;1421:110–20.

    Article  CAS  PubMed  Google Scholar 

  162. Takeda S, et al. Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension. 2009;54(6):1345–52.

    Article  CAS  PubMed  Google Scholar 

  163. Tsukuda K, et al. Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation. Hypertension. 2009;54(4):782–7.

    Article  CAS  PubMed  Google Scholar 

  164. Wang J, et al. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007;117(11):3393–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ongali B, et al. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis. 2014;68:126–36.

    Article  CAS  PubMed  Google Scholar 

  166. Braszko JJ, et al. Angiotensin II-(3-8)-hexapeptide affects motor activity, performance of passive avoidance and a conditioned avoidance response in rats. Neuroscience. 1988;27(3):777–83.

    Article  CAS  PubMed  Google Scholar 

  167. Wright JW, et al. Angiotensin II(3-8) (ANG IV) hippocampal binding: potential role in the facilitation of memory. Brain Res Bull. 1993;32(5):497–502.

    Article  CAS  PubMed  Google Scholar 

  168. Wayner MJ, et al. Angiotensin IV enhances LTP in rat dentate gyrus in vivo. Peptides. 2001;22(9):1403–14.

    Article  CAS  PubMed  Google Scholar 

  169. Chai SY, et al. Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase. BMC Neurosci. 2008;9 Suppl 2:S14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer’s and Parkinson’s diseases. Prog Neurobiol. 2015;125:26–46.

    Article  CAS  PubMed  Google Scholar 

  171. Smith PJ, et al. Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension. 2010;55(6):1331–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bink DI, et al. Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition. J Cereb Blood Flow Metab. 2013;33(11):1666–84.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Barnes JM, et al. Angiotensin-converting enzyme inhibition, angiotensin, and cognition. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S63–71.

    Article  CAS  PubMed  Google Scholar 

  174. Mogi M, et al. Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun. 2008;375(3):446–9.

    Article  CAS  PubMed  Google Scholar 

  175. Singh B, et al. Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s disease type: possible involvement of PPAR-gamma agonistic property. J Renin Angiotensin Aldosterone Syst. 2013;14(2):124–36.

    Article  CAS  PubMed  Google Scholar 

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Obari, D., Ozcelik, S.O., Girouard, H., Hamel, E. (2016). Cognitive Dysfunction and Dementia in Animal Models of Hypertension. In: Girouard, H. (eds) Hypertension and the Brain as an End-Organ Target. Springer, Cham. https://doi.org/10.1007/978-3-319-25616-0_5

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