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GeroScience

, Volume 39, Issue 4, pp 359–372 | Cite as

Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease

  • Anna Csiszar
  • Stefano Tarantini
  • Gábor A. Fülöp
  • Tamas Kiss
  • M. Noa Valcarcel-Ares
  • Veronica Galvan
  • Zoltan Ungvari
  • Andriy YabluchanskiyEmail author
Neuroscience meets GeroScience

Abstract

Hypertension in the elderly substantially increases both the risk of vascular cognitive impairment (VCI) and Alzheimer’s disease (AD); however, the underlying mechanisms are not completely understood. This review discusses the effects of hypertension on structural and functional integrity of cerebral microcirculation, including hypertension-induced alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage (capillary rarefaction, blood-brain barrier disruption), and the genesis of cerebral microhemorrhages and their potential role in exacerbation of cognitive decline associated with AD. Understanding and targeting the hypertension-induced cerebromicrovascular alterations that are involved in the onset and progression of AD and contribute to cognitive impairment are expected to have a major role in preserving brain health in high-risk older individuals.

Keywords

Functional hyperemia Neurovascular coupling Angiotensin II High blood pressure Hypertension VCID Endothelial dysfunction Microcirculation Alzheimer’s disease 

Notes

Acknowledgements

This work was supported by grants from the American Heart Association (to ST, MNVA, AC, and ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG047879 to AC; R01-AG038747), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the NIA-supported Oklahoma Nathan Shock Center (3P30AG050911-02S1), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC), the Oklahoma Shared Clinical and Translational Resources (to AY; NIGMS U54GM104938), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU, and AY), the Reynolds Foundation (to ZU, AC and AY), and the Presbyterian Health Foundation (to AC, ZU, and AY). We also acknowledge support from the Merit Review Award I01 BX002211-01A2 from the US Department of Veterans Affairs (to VG), the William & Ella Owens Medical Research Foundation (VG), the San Antonio Nathan Shock Center of Excellence in the Biology of Aging (2 P30 AG013319-21) (VG), and the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer’s Fund in memory of Jo Nell Bailey (VG).

References

  1. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE (2017) IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. GeroscienceGoogle Scholar
  2. Austin SA, Santhanam AV, Hinton DJ, Choi DS, Katusic ZS (2013) Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J Neurochem 127:691–700PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A (2012) Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol Biol Med Sci 67:313–329CrossRefGoogle Scholar
  4. Balbi M, Ghosh M, Longden TA, Jativa Vega M, Gesierich B, Hellal F, Lourbopoulos A, Nelson MT, Plesnila N (2015) Dysfunction of mouse cerebral arteries during early aging. J Cereb Blood Flow Metab 35:1445–1453PubMedPubMedCentralCrossRefGoogle Scholar
  5. Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, Tamas A, Helyes Z, Reglodi D, Sonntag WE, Csiszar A, Ungvari Z (2015) Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 70:665–674PubMedCrossRefGoogle Scholar
  6. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427PubMedPubMedCentralCrossRefGoogle Scholar
  8. Benedictus MR, Goos JD, Binnewijzend MA, Muller M, Barkhof F, Scheltens P, Prins ND, van der Flier WM (2013) Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer’s disease. Neurobiol Aging 34:2488–2494PubMedCrossRefGoogle Scholar
  9. Bennis MT, Schneider A, Victoria B, Do A, Wiesenborn DS, Spinel L, Gesing A, Kopchick JJ, Siddiqi SA, Masternak MM (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience 39:51–59PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brickman AM, Guzman VA, Gonzalez-Castellon M, Razlighi Q, Gu Y, Narkhede A, Janicki S, Ichise M, Stern Y, Manly JJ, Schupf N, Marshall RS (2015) Cerebral autoregulation, beta amyloid, and white matter hyperintensities are interrelated. Neurosci Lett 592:54–58PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brown WR (2010) A review of string vessels or collapsed, empty basement membrane tubes. J Alzheimers Dis 21:725–739PubMedPubMedCentralCrossRefGoogle Scholar
  12. Brown WR, Thore CR (2011) Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 37:56–74PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bruce-Keller AJ, White CL, Gupta S, Knight AG, Pistell PJ, Ingram DK, Morrison CD, Keller JN (2010) NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med 49:22–30PubMedPubMedCentralCrossRefGoogle Scholar
  14. Buee L, Hof PR, Bouras C, Delacourte A, Perl DP, Morrison JH, Fillit HM (1994) Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol 87:469–480PubMedCrossRefGoogle Scholar
  15. Callisaya ML, Launay CP, Srikanth VK, Verghese J, Allali G, Beauchet O (2017) Cognitive status, fast walking speed and walking speed reserve—the Gait and Alzheimer Interactions Tracking (GAIT) study. Geroscience 39:231–239PubMedPubMedCentralCrossRefGoogle Scholar
  16. Capone C, Faraco G, Peterson JR, Coleman C, Anrather J, Milner TA, Pickel VM, Davisson RL, Iadecola C (2012) Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension. J Neurosci 32:4878–4886PubMedPubMedCentralCrossRefGoogle Scholar
  17. Carnevale D, Lembo G (2011) ‘Alzheimer-like’ pathology in a murine model of arterial hypertension. Biochem Soc Trans 39:939–944PubMedCrossRefGoogle Scholar
  18. Carnevale D, Mascio G, Ajmone-Cat MA, D'Andrea I, Cifelli G, Madonna M, Cocozza G, Frati A, Carullo P, Carnevale L, Alleva E, Branchi I, Lembo G, Minghetti L (2012a) Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging 33:205 e19–205 e29CrossRefGoogle Scholar
  19. Carnevale D, Mascio G, D'Andrea I, Fardella V, Bell RD, Branchi I, Pallante F, Zlokovic B, Yan SS, Lembo G (2012b) Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 60:188–197PubMedPubMedCentralCrossRefGoogle Scholar
  20. Carreno-Muller E, Herrera AJ, de Pablos RM, Tomas-Camardiel M, Venero JL, Cano J, Machado A (2003) Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia. J Neurochem 84:1201–1214PubMedCrossRefGoogle Scholar
  21. Castillo-Carranza DL, Nilson AN, Van Skike CE, Jahrling JB, Patel K, Garach P, Gerson JE, Sengupta U, Abisambra J, Nelson P, Troncoso J, Ungvari Z, Galvan V, Kayed R (2017) Cerebral microvascular accumulation of tau oligomers in Alzheimer’s disease and related tauopathies. Aging Dis 8:257–266PubMedPubMedCentralCrossRefGoogle Scholar
  22. Caunca MR, Del Brutto V, Gardener H, Shah N, Dequatre-Ponchelle N, Cheung YK, Elkind MS, Brown TR, Cordonnier C, Sacco RL, Wright CB (2016) Cerebral microbleeds, vascular risk factors, and magnetic resonance imaging markers: the Northern Manhattan Study. J Am Heart Assoc 5(9).  https://doi.org/10.1161/JAHA.116.003477
  23. Chai C, Wang Z, Fan L, Zhang M, Chu Z, Zuo C, Liu L, Mark Haacke E, Guo W, Shen W, Xia S (2016) Increased number and distribution of cerebral microbleeds is a risk factor for cognitive dysfunction in hemodialysis patients: a longitudinal study. Medicine (Baltimore) 95:e2974CrossRefGoogle Scholar
  24. Chen BR, Kozberg MG, Bouchard MB, Shaik MA, Hillman EM (2014) A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc 3:e000787PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chiang GC, Mao X, Kang G, Chang E, Pandya S, Vallabhajosula S, Isaacson R, Ravdin LD, Shungu DC (2017) Relationships among cortical glutathione levels, brain amyloidosis, and memory in healthy older adults investigated in vivo with 1H-MRS and Pittsburgh compound-B PET. AJNR Am J Neuroradiol 38:1130–1137PubMedCrossRefGoogle Scholar
  26. Chrissobolis S, Banfi B, Sobey CG, Faraci FM (2012) Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain. J Appl Physiol (1985) 113:184–191CrossRefGoogle Scholar
  27. Cordonnier C, Al-Shahi Salman R, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130:1988–2003PubMedCrossRefGoogle Scholar
  28. Csiszar A, Ungvari Z, Edwards JG, Kaminski PM, Wolin MS, Koller A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90:1159–1166PubMedCrossRefGoogle Scholar
  29. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2004) Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. Physiol Genomics 17:21–30PubMedCrossRefGoogle Scholar
  30. Csiszar A, Tucsek Z, Toth P, Sosnowska D, Gautam T, Koller A, Deak F, Sonntag WE, Ungvari Z (2013a) Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in beta-amyloid generation and Alzheimer’s disease. Am J Physiol Heart Circ Physiol 305:H1120–H1130PubMedPubMedCentralCrossRefGoogle Scholar
  31. Csiszar A, Sosnowska D, Tucsek Z, Gautam T, Toth P, Losonczy G, Colman RJ, Weindruch R, Anderson RM, Sonntag WE, Ungvari Z (2013b) Circulating factors induced by caloric restriction in the nonhuman primate Macaca mulatta activate angiogenic processes in endothelial cells. J Gerontol A Biol Sci Med Sci 68:235–249PubMedCrossRefGoogle Scholar
  32. Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z, Toth P, Losonczy G, Koller A, Reglodi D, Giles CB, Wren JD, Sonntag WE, Ungvari Z (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292–H306PubMedPubMedCentralCrossRefGoogle Scholar
  33. Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA, Deerinck TJ, Smirnoff DS, Bedard C, Hakozaki H, Gonias Murray S, Ling JB, Lassmann H, Degen JL, Ellisman MH, Akassoglou K (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227PubMedPubMedCentralCrossRefGoogle Scholar
  34. de la Torre JC (2010) Vascular risk factor detection and control may prevent Alzheimer’s disease. Ageing Res Rev 9:218–225PubMedCrossRefGoogle Scholar
  35. de la Torre JC (2012) Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer’s disease. J Alzheimers Dis 32:553–567PubMedGoogle Scholar
  36. de la Torre JC (2013) Vascular risk factors: a ticking time bomb to Alzheimer’s disease. Am J Alzheimers Dis Other Demen 28:551–559PubMedCrossRefGoogle Scholar
  37. de la Torre JC (2017) Are major dementias triggered by poor blood flow to the brain? Theoretical considerations. J Alzheimers Dis 57:353–371PubMedCrossRefGoogle Scholar
  38. Deepa SS, Bhaskaran S, Espinoza S, Brooks SV, McArdle A, Jackson MJ, Van Remmen H, Richardson A (2017) A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse. Geroscience 39:187–198PubMedPubMedCentralCrossRefGoogle Scholar
  39. den Abeelen AS, Lagro J, van Beek AH, Claassen JA (2014) Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer’s disease. Curr Alzheimer Res 11:11–17CrossRefGoogle Scholar
  40. Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF (2015) Vascular dysfunction in the pathogenesis of Alzheimer’s disease—a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol Dis 82:593–606PubMedCrossRefGoogle Scholar
  41. Diaz-Ruiz C, Wang J, Ksiezak-Reding H, Ho L, Qian X, Humala N, Thomas S, Martinez-Martin P, Pasinetti GM (2009) Role of hypertension in aggravating Abeta neuropathology of AD type and tau-mediated motor impairment. Cardiovasc Psychiatry Neurol 2009:107286PubMedPubMedCentralCrossRefGoogle Scholar
  42. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Alzheimer’s Disease Cooperative Study Steering C, Siemers E, Sethuraman G, Mohs R, Semagacestat Study G (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350PubMedCrossRefGoogle Scholar
  43. Enager P, Piilgaard H, Offenhauser N, Kocharyan A, Fernandes P, Hamel E, Lauritzen M (2009) Pathway-specific variations in neurovascular and neurometabolic coupling in rat primary somatosensory cortex. J Cereb Blood Flow Metab 29:976–986PubMedCrossRefGoogle Scholar
  44. Fabiani M, Gordon BA, Maclin EL, Pearson MA, Brumback-Peltz CR, Low KA, McAuley E, Sutton BP, Kramer AF, Gratton G (2013) Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study. Neuroimage 85(Pt 1):592–607Google Scholar
  45. Faraco G, Iadecola C (2013) Hypertension: a harbinger of stroke and dementia. Hypertension 62:810–817PubMedCrossRefGoogle Scholar
  46. Faraco G, Park L, Zhou P, Luo W, Paul SM, Anrather J, Iadecola C (2016) Hypertension enhances Abeta-induced neurovascular dysfunction, promotes beta-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab 36:241–252PubMedPubMedCentralCrossRefGoogle Scholar
  47. Farkas E, De Jong GI, Apro E, De Vos RA, Steur EN, Luiten PG (2000) Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer’s disease, Parkinson’s disease, and experimental hypertension. What is the functional link? Ann N Y Acad Sci 903:72–82PubMedCrossRefGoogle Scholar
  48. Feihl F, Liaudet L, Waeber B (2009) The macrocirculation and microcirculation of hypertension. Curr Hypertens Rep 11:182–189PubMedCrossRefGoogle Scholar
  49. Fischer VW, Siddiqi A, Yusufaly Y (1990) Altered angioarchitecture in selected areas of brains with Alzheimer’s disease. Acta Neuropathol 79:672–679PubMedCrossRefGoogle Scholar
  50. Fonseca AC, Ferreiro E, Oliveira CR, Cardoso SM, Pereira CF (1832) Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta 2013:2191–2203Google Scholar
  51. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R (1998) Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 352:1347–1351PubMedCrossRefGoogle Scholar
  52. Fotuhi M, Hachinski V, Whitehouse PJ (2009) Changing perspectives regarding late-life dementia. Nat Rev Neurol 5:649–658PubMedCrossRefGoogle Scholar
  53. Galvan V, Hart MJ (2016) Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer’s disease. Biochim Biophys Acta 1862:992–1007PubMedCrossRefGoogle Scholar
  54. Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985) 100:328–335CrossRefGoogle Scholar
  55. Girouard H, Park L, Anrather J, Zhou P, Iadecola C (2006) Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through nox-2-derived radicals. Arterioscler Thromb Vasc Biol 26:826–832PubMedCrossRefGoogle Scholar
  56. Girouard H, Park L, Anrather J, Zhou P, Iadecola C (2007) Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol 27:303–309PubMedCrossRefGoogle Scholar
  57. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713PubMedPubMedCentralCrossRefGoogle Scholar
  58. Grimmig B, Kim SH, Nash K, Bickford PC, Douglas Shytle R (2017) Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. Geroscience 39:19–32PubMedPubMedCentralCrossRefGoogle Scholar
  59. Guo Z, Qiu C, Viitanen M, Fastbom J, Winblad B, Fratiglioni L (2001) Blood pressure and dementia in persons 75+ years old: 3-year follow-up results from the Kungsholmen Project. J Alzheimers Dis 3:585–591PubMedCrossRefGoogle Scholar
  60. Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 36:216–227PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hancock SE, Friedrich MG, Mitchell TW, Truscott RJ, Else PL (2017) The phospholipid composition of the human entorhinal cortex remains relatively stable over 80 years of adult aging. Geroscience 39:73–82PubMedPubMedCentralCrossRefGoogle Scholar
  62. Harper SL, Bohlen HG (1984) Microvascular adaptation in the cerebral cortex of adult spontaneously hypertensive rats. Hypertension 6:408–419PubMedCrossRefGoogle Scholar
  63. Hirao K, Ohnishi T, Hirata Y, Yamashita F, Mori T, Moriguchi Y, Matsuda H, Nemoto K, Imabayashi E, Yamada M, Iwamoto T, Arima K, Asada T (2005) The prediction of rapid conversion to Alzheimer’s disease in mild cognitive impairment using regional cerebral blood flow SPECT. NeuroImage 28:1014–1021PubMedCrossRefGoogle Scholar
  64. Hock C, Villringer K, Muller-Spahn F, Wenzel R, Heekeren H, Schuh-Hofer S, Hofmann M, Minoshima S, Schwaiger M, Dirnagl U, Villringer A (1997) Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer’s disease monitored by means of near-infrared spectroscopy (NIRS)—correlation with simultaneous rCBF-PET measurements. Brain Res 755:293–303PubMedCrossRefGoogle Scholar
  65. Hsu CY, Huang CC, Chan WL, Huang PH, Chiang CH, Chen TJ, Chung CM, Lin SJ, Chen JW, Leu HB (2013) Angiotensin-receptor blockers and risk of Alzheimer’s disease in hypertension population. Circ J 77:405–410PubMedCrossRefGoogle Scholar
  66. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360PubMedCrossRefGoogle Scholar
  67. Iadecola C (2014) Hypertension and dementia. Hypertension 64:3–5PubMedPubMedCentralCrossRefGoogle Scholar
  68. Iadecola C, Park L, Capone C (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40:S40–S44PubMedCrossRefGoogle Scholar
  69. Israeli-Korn SD, Masarwa M, Schechtman E, Abuful A, Strugatsky R, Avni S, Farrer LA, Friedland RP, Inzelberg R (2010) Hypertension increases the probability of Alzheimer’s disease and of mild cognitive impairment in an Arab community in northern Israel. Neuroepidemiology 34:99–105PubMedCrossRefGoogle Scholar
  70. Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, Massaro JM, DeCarli C (2004) Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study. Stroke 35:1831–1835PubMedCrossRefGoogle Scholar
  71. Joas E, Backman K, Gustafson D, Ostling S, Waern M, Guo X, Skoog I (2012) Blood pressure trajectories from midlife to late life in relation to dementia in women followed for 37 years. Hypertension 59:796–801PubMedCrossRefGoogle Scholar
  72. Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234:851–859PubMedPubMedCentralCrossRefGoogle Scholar
  73. Joshi G, Gan KA, Johnson DA, Johnson JA (2015) Increased Alzheimer’s disease-like pathology in the APP/PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36:664–679PubMedCrossRefGoogle Scholar
  74. Kane AE, Gregson E, Theou O, Rockwood K, Howlett SE (2017) The association between frailty, the metabolic syndrome, and mortality over the lifespan. Geroscience 39:221–229PubMedPubMedCentralCrossRefGoogle Scholar
  75. Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Yla-Herttuala S, Tanila H, Levonen AL, Koistinaho M, Koistinaho J (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 106:16505–16510PubMedPubMedCentralCrossRefGoogle Scholar
  76. Kazama K, Wang G, Frys K, Anrather J, Iadecola C (2003) Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 285:H1890–H1899PubMedCrossRefGoogle Scholar
  77. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95:1019–1026PubMedCrossRefGoogle Scholar
  78. Khan AS, Sane DC, Wannenburg T, Sonntag WE (2002) Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res 54:25–35PubMedCrossRefGoogle Scholar
  79. Kim S, Myers L, Wyckoff J, Cherry KE, Jazwinski SM (2017) The frailty index outperforms DNA methylation age and its derivatives as an indicator of biological age. Geroscience 39:83–92PubMedPubMedCentralCrossRefGoogle Scholar
  80. Kimbrough IF, Robel S, Roberson ED, Sontheimer H (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease. Brain 138:3716–3733PubMedPubMedCentralCrossRefGoogle Scholar
  81. Konopka AR, Laurin JL, Musci RV, Wolff CA, Reid JJ, Biela LM, Zhang Q, Peelor FF 3rd, Melby CL, Hamilton KL, Miller BF (2017) Influence of Nrf2 activators on subcellular skeletal muscle protein and DNA synthesis rates after 6 weeks of milk protein feeding in older adults. Geroscience 39:175–186PubMedPubMedCentralCrossRefGoogle Scholar
  82. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL Jr (1978) Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Phys 234:H371–H383Google Scholar
  83. Kurata T, Lukic V, Kozuki M, Wada D, Miyazaki K, Morimoto N, Ohta Y, Deguchi K, Ikeda Y, Kamiya T, Abe K (2014) Telmisartan reduces progressive accumulation of cellular amyloid beta and phosphorylated tau with inflammatory responses in aged spontaneously hypertensive stroke resistant rat. J Stroke Cerebrovasc Dis 23:2580–2590PubMedCrossRefGoogle Scholar
  84. Laske C (2014) Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N Engl J Med 370:1459PubMedCrossRefGoogle Scholar
  85. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ (2000) Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 21:49–55PubMedCrossRefGoogle Scholar
  86. Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M, Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter JD, Fox PT, Galvan V (2013) Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J Cereb Blood Flow Metab 33:1412–1421PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lin AL, Jahrling JB, Zhang W, DeRosa N, Bakshi V, Romero P, Galvan V, Richardson A (2017) Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease. J Cereb Blood Flow Metab 37:217–226PubMedCrossRefGoogle Scholar
  88. Liu X, Bhatt T, Wang S, Yang F, Pai YC (2017) Retention of the “first-trial effect” in gait-slip among community-living older adults. Geroscience 39:93–102PubMedPubMedCentralCrossRefGoogle Scholar
  89. Lyros E, Bakogiannis C, Liu Y, Fassbender K (2014) Molecular links between endothelial dysfunction and neurodegeneration in Alzheimer’s disease. Curr Alzheimer Res 11:18–26PubMedCrossRefGoogle Scholar
  90. Mackic JB, Weiss MH, Miao W, Kirkman E, Ghiso J, Calero M, Bading J, Frangione B, Zlokovic BV (1998) Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer’s amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem 70:210–215PubMedCrossRefGoogle Scholar
  91. Mackic JB, Bading J, Ghiso J, Walker L, Wisniewski T, Frangione B, Zlokovic BV (2002) Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer’s disease lesions. Vasc Pharmacol 38:303–313CrossRefGoogle Scholar
  92. Marr RA, Hafez DM (2014) Amyloid-beta and Alzheimer’s disease: the role of neprilysin-2 in amyloid-beta clearance. Front Aging Neurosci 6:187PubMedPubMedCentralGoogle Scholar
  93. Mathiesen C, Caesar K, Akgoren N, Lauritzen M (1998) Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex. J Physiol 512(Pt 2):555–566PubMedPubMedCentralCrossRefGoogle Scholar
  94. Meschiari CA, Ero OK, Pan H, Finkel T, Lindsey ML (2017) The impact of aging on cardiac extracellular matrix. Geroscience 39:7–18PubMedPubMedCentralCrossRefGoogle Scholar
  95. Modrick ML, Didion SP, Sigmund CD, Faraci FM (2009) Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol 296:H1914–H1919PubMedPubMedCentralCrossRefGoogle Scholar
  96. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:296–302PubMedPubMedCentralCrossRefGoogle Scholar
  97. Mueller SM, Heistad DD (1980) Effect of chronic hypertension on the blood-brain barrier. Hypertension 2:809–812PubMedCrossRefGoogle Scholar
  98. Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV (1862) Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta 2016:887–900Google Scholar
  99. Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rosa-Neto P, Tong XK, Hamel E (2008) Complete rescue of cerebrovascular function in aged Alzheimer’s disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci 28:9287–9296PubMedCrossRefGoogle Scholar
  100. Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C (2001) A beta-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 281:H2417–H2424PubMedGoogle Scholar
  101. Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C (2002a) Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol 283:H315–H323PubMedCrossRefGoogle Scholar
  102. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C (2002b) Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 9:61–68PubMedCrossRefGoogle Scholar
  103. Papadopoulos P, Tong XK, Hamel E (2014) Selective benefits of simvastatin in bitransgenic APPSwe, Ind/TGF-beta1 mice. Neurobiol Aging 35:203–212PubMedCrossRefGoogle Scholar
  104. Papadopoulos P, Tong XK, Imboden H, Hamel E (2016) Losartan improves cerebrovascular function in a mouse model of Alzheimer’s disease with combined overproduction of amyloid-beta and transforming growth factor-beta1. J Cereb Blood Flow Metab. 2016:271678X16658489Google Scholar
  105. Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25:1769–1777PubMedCrossRefGoogle Scholar
  106. Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27:1908–1918PubMedCrossRefGoogle Scholar
  107. Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A 105:1347–1352PubMedPubMedCentralCrossRefGoogle Scholar
  108. Park L, Zhou P, Koizumi K, El Jamal S, Previti ML, Van Nostrand WE, Carlson G, Iadecola C (2013) Brain and circulating levels of Abeta1-40 differentially contribute to vasomotor dysfunction in the mouse brain. Stroke 44:198–204PubMedCrossRefGoogle Scholar
  109. Park L, Koizumi K, El Jamal S, Zhou P, Previti ML, Van Nostrand WE, Carlson G, Iadecola C (2014) Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45:1815–1821PubMedPubMedCentralCrossRefGoogle Scholar
  110. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R (2008) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A 105:2325–2330PubMedPubMedCentralCrossRefGoogle Scholar
  111. Pena Silva RA, Chu Y, Miller JD, Mitchell IJ, Penninger JM, Faraci FM, Heistad DD (2012) Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke 43:3358–3363PubMedPubMedCentralCrossRefGoogle Scholar
  112. Perrott KM, Wiley CD, Desprez PY, Campisi J (2017) Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience 39:161–173PubMedPubMedCentralCrossRefGoogle Scholar
  113. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ (2000) Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging 21:57–62PubMedGoogle Scholar
  114. Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE (2008) Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 65:790–795PubMedCrossRefGoogle Scholar
  115. Petzold GC, Murthy VN (2011) Role of astrocytes in neurovascular coupling. Neuron 71:782–797PubMedCrossRefGoogle Scholar
  116. Pires PW, Dams Ramos CM, Matin N, Dorrance AM (2013) The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol 304:H1598–H1614PubMedPubMedCentralCrossRefGoogle Scholar
  117. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32PubMedCrossRefGoogle Scholar
  118. Podlutsky A, Valcarcel-Ares MN, Yancey K, Podlutskaya V, Nagykaldi E, Gautam T, Miller RA, Sonntag WE, Csiszar A, Ungvari Z (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience 39:147–160PubMedPubMedCentralCrossRefGoogle Scholar
  119. Rancillac A, Geoffroy H, Rossier J (2012) Impaired neurovascular coupling in the APPxPS1 mouse model of Alzheimer’s disease. Curr Alzheimer Res 9:1221–1230PubMedCrossRefGoogle Scholar
  120. Raskin J, Cummings J, Hardy J, Schuh K, Dean RA (2015) Neurobiology of Alzheimer’s disease: integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Curr Alzheimer Res 12:712–722PubMedPubMedCentralCrossRefGoogle Scholar
  121. Religa P, Cao R, Religa D, Xue Y, Bogdanovic N, Westaway D, Marti HH, Winblad B, Cao Y (2013) VEGF significantly restores impaired memory behavior in Alzheimer’s mice by improvement of vascular survival. Sci Rep 3:2053PubMedPubMedCentralCrossRefGoogle Scholar
  122. Richardson A, Galvan V, Lin AL, Oddo S (2015) How longevity research can lead to therapies for Alzheimer’s disease: the rapamycin story. Exp Gerontol 68:51–58PubMedCrossRefGoogle Scholar
  123. Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2:149–168PubMedCrossRefGoogle Scholar
  124. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ (1993) beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A 90:10836–10840PubMedPubMedCentralCrossRefGoogle Scholar
  125. Rombouts SA, Barkhof F, Veltman DJ, Machielsen WC, Witter MP, Bierlaagh MA, Lazeron RH, Valk J, Scheltens P (2000) Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am J Neuroradiol 21:1869–1875PubMedGoogle Scholar
  126. Romero JR, Preis SR, Beiser A, DeCarli C, Viswanathan A, Martinez-Ramirez S, Kase CS, Wolf PA, Seshadri S (2014) Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 45:1492–1494PubMedPubMedCentralCrossRefGoogle Scholar
  127. Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F (1999) MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 52:991–994PubMedCrossRefGoogle Scholar
  128. Sagare AP, Bell RD, Zlokovic BV (2013a) Neurovascular defects and faulty amyloid-beta vascular clearance in Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S87–100PubMedPubMedCentralGoogle Scholar
  129. Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV (2013b) Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 4:2932PubMedPubMedCentralCrossRefGoogle Scholar
  130. Schreiber S, Drukarch B, Garz C, Niklass S, Stanaszek L, Kropf S, Bueche C, Held F, Vielhaber S, Attems J, Reymann KG, Heinze HJ, Carare RO, Wilhelmus MM (2014) Interplay between age, cerebral small vessel disease, parenchymal amyloid-beta, and tau pathology: longitudinal studies in hypertensive stroke-prone rats. J Alzheimers Dis 42(Suppl 3):S205–S215PubMedGoogle Scholar
  131. Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ, Frosch MP, Hyman BT, Moskowitz MA, Ayata C (2007) Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain 130:2310–2319PubMedCrossRefGoogle Scholar
  132. Shobin E, Bowley MP, Estrada LI, Heyworth NC, Orczykowski ME, Eldridge SA, Calderazzo SM, Mortazavi F, Moore TL, Rosene DL (2017) Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. Geroscience 39:199–220PubMedPubMedCentralCrossRefGoogle Scholar
  133. Sierra F, Kohanski R (2017) Geroscience and the trans-NIH Geroscience Interest Group, GSIG. Geroscience 39:1–5PubMedPubMedCentralCrossRefGoogle Scholar
  134. Skoog I, Gustafson D (2006) Update on hypertension and Alzheimer’s disease. Neurol Res 28:605–611PubMedCrossRefGoogle Scholar
  135. Sokolova IA, Manukhina EB, Blinkov SM, Koshelev VB, Pinelis VG, Rodionov IM (1985) Rarefication of the arterioles and capillary network in the brain of rats with different forms of hypertension. Microvasc Res 30:1–9PubMedCrossRefGoogle Scholar
  136. Sonntag WE, Lynch CD, Cooney PT, Hutchins PM (1997) Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. Endocrinology 138:3515–3520PubMedCrossRefGoogle Scholar
  137. Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5:27PubMedPubMedCentralCrossRefGoogle Scholar
  138. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND (2013) Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 81:904–909PubMedPubMedCentralCrossRefGoogle Scholar
  139. Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM, Hunsaker JC 3rd (1995) Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension. J Neurol Sci 131:162–169PubMedCrossRefGoogle Scholar
  140. Springo Z, Toth P, Tarantini S, Ashpole NM, Tucsek Z, Sonntag WE, Csiszar A, Koller A, Ungvari ZI (2015a) Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries. J Cereb Blood Flow Metab 35:527–530PubMedPubMedCentralCrossRefGoogle Scholar
  141. Springo Z, Tarantini S, Toth P, Tucsek Z, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015b) Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci 70:1355–1359PubMedPubMedCentralCrossRefGoogle Scholar
  142. Stobart JL, Lu L, Anderson HD, Mori H, Anderson CM (2013) Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 110:3149–3154PubMedPubMedCentralCrossRefGoogle Scholar
  143. Suzuki K, Masawa N, Sakata N, Takatama M (2003) Pathologic evidence of microvascular rarefaction in the brain of renal hypertensive rats. J Stroke Cerebrovasc Dis 12:8–16PubMedCrossRefGoogle Scholar
  144. Sveinbjornsdottir S, Sigurdsson S, Aspelund T, Kjartansson O, Eiriksdottir G, Valtysdottir B, Lopez OL, van Buchem MA, Jonsson PV, Gudnason V, Launer LJ (2008) Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 79:1002–1006PubMedCrossRefGoogle Scholar
  145. Takemori K, Murakami T, Kometani T, Ito H (2013) Possible involvement of oxidative stress as a causative factor in blood-brain barrier dysfunction in stroke-prone spontaneously hypertensive rats. Microvasc Res 90:169–172PubMedCrossRefGoogle Scholar
  146. Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges E, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35:1871–1881PubMedPubMedCentralCrossRefGoogle Scholar
  147. Tarantini S, Tucsek Z, Valcarcel-Ares M, Toth P, Gautam T, Giles C, Ballabh P, Wei Y, Wren J, Ashpole N, Sonntag W, Ungvari Z, Csiszar A (2016a) Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38:273–289CrossRefGoogle Scholar
  148. Tarantini S, Tran CH, Gordon GR, Ungvari Z, Csiszar A (2016b) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol.  https://doi.org/10.1016/j.exger.2016.11.004
  149. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z (2017) IGF-1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell 16:469–479PubMedPubMedCentralCrossRefGoogle Scholar
  150. Tarumi T, Dunsky DI, Khan MA, Liu J, Hill C, Armstrong K, Martin-Cook K, Cullum CM, Zhang R (2014) Dynamic cerebral autoregulation and tissue oxygenation in amnestic mild cognitive impairment. J Alzheimers Dis 41(3):765–778PubMedGoogle Scholar
  151. Tenk J, Rostas I, Furedi N, Miko A, Solymar M, Soos S, Gaszner B, Feller D, Szekely M, Petervari E, Balasko M (2017) Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia. Geroscience 39:61–72PubMedPubMedCentralCrossRefGoogle Scholar
  152. Tong XK, Lecrux C, Rosa-Neto P, Hamel E (2012) Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J Neurosci 32:4705–4715PubMedCrossRefGoogle Scholar
  153. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013a) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33:1732–1742PubMedPubMedCentralCrossRefGoogle Scholar
  154. Toth P, Csiszar A, Tucsek Z, Sosnowska D, Gautam T, Koller A, Schwartzman ML, Sonntag WE, Ungvari Z (2013b) Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice. Am J Physiol Heart Circ Physiol 305:H1698–H1708PubMedPubMedCentralCrossRefGoogle Scholar
  155. Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2014a) IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34:1887–1897PubMedPubMedCentralCrossRefGoogle Scholar
  156. Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari ZI (2014b) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidase. Am J Physiol Heart Circ Physiol 306:H299–H308PubMedCrossRefGoogle Scholar
  157. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015a) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14:400–408PubMedPubMedCentralCrossRefGoogle Scholar
  158. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015b) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044PubMedPubMedCentralCrossRefGoogle Scholar
  159. Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015c) Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 309:H1837–H1845PubMedPubMedCentralCrossRefGoogle Scholar
  160. Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312:H1–H20PubMedCrossRefGoogle Scholar
  161. Troen AM, Shea-Budgell M, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH (2008) B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proc Natl Acad Sci U S A 105:12474–12479PubMedPubMedCentralCrossRefGoogle Scholar
  162. Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352PubMedPubMedCentralCrossRefGoogle Scholar
  163. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A (2007) Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293:H37–H47PubMedCrossRefGoogle Scholar
  164. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65:1028–1041PubMedCrossRefGoogle Scholar
  165. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, Sonntag WE, Lakatta E, Csiszar A (2011a) Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66:866–875PubMedCrossRefGoogle Scholar
  166. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A (2011b) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301:H363–H372PubMedPubMedCentralCrossRefGoogle Scholar
  167. Ungvari ZI, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, Ballabh P, Recchia FA, Wilkerson DC, Sonntag WE, Pearson KJ, de Cabo R, Csiszar A (2011c) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300:H1133–H1140PubMedPubMedCentralCrossRefGoogle Scholar
  168. Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE (2013) Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68:877–891PubMedCrossRefGoogle Scholar
  169. Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S, Kiss T, Farkas E, Csiszar A, Yabluchanskiy A (2017a) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience 39:33–42PubMedPubMedCentralCrossRefGoogle Scholar
  170. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017b) Cerebral microhemorrhages: mechanisms, consequences and prevention. Am J Physiol Heart Circ Physiol in pressGoogle Scholar
  171. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DE, Kaeberlein M (2017a) A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39:117–127PubMedPubMedCentralCrossRefGoogle Scholar
  172. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DE, Kaeberlein M (2017b) Asymptomatic heart valve dysfunction in healthy middle-aged companion dogs and its implications for cardiac aging. Geroscience 39:43–50PubMedPubMedCentralCrossRefGoogle Scholar
  173. Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A (2012) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67:821–829PubMedPubMedCentralCrossRefGoogle Scholar
  174. van Dijk EJ, Breteler MM, Schmidt R, Berger K, Nilsson LG, Oudkerk M, Pajak A, Sans S, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Launer LJ, Hofman A, Consortium C (2004) The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension 44:625–630PubMedCrossRefGoogle Scholar
  175. Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM (2008) Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 70:1208–1214PubMedCrossRefGoogle Scholar
  176. Viana IM, de Almeida ME, Lins MP, dos Santos Reis MD, de Araujo Vieira LF, Smaniotto S (2015) Combined effect of insulin-like growth factor-1 and CC chemokine ligand 2 on angiogenic events in endothelial cells. PLoS One 10:e0121249PubMedPubMedCentralCrossRefGoogle Scholar
  177. Wakisaka Y, Miller JD, Chu Y, Baumbach GL, Wilson S, Faraci FM, Sigmund CD, Heistad DD (2008) Oxidative stress through activation of NAD(P)H oxidase in hypertensive mice with spontaneous intracranial hemorrhage. J Cereb Blood Flow Metab 28:1175–1185PubMedPubMedCentralCrossRefGoogle Scholar
  178. Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD (2010) Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. J Cereb Blood Flow Metab 30:56–69PubMedCrossRefGoogle Scholar
  179. Wells JA, Christie IN, Hosford PS, Huckstepp RT, Angelova PR, Vihko P, Cork SC, Abramov AY, Teschemacher AG, Kasparov S, Lythgoe MF, Gourine AV (2015) A critical role for purinergic signalling in the mechanisms underlying generation of BOLD fMRI responses. J Neurosci 35:5284–5292PubMedPubMedCentralCrossRefGoogle Scholar
  180. White CL, Pistell PJ, Purpera MN, Gupta S, Fernandez-Kim SO, Hise TL, Keller JN, Ingram DK, Morrison CD, Bruce-Keller AJ (2009) Effects of high fat diet on Morris maze performance, oxidative stress, and inflammation in rats: contributions of maternal diet. Neurobiol Dis 35:3–13PubMedPubMedCentralCrossRefGoogle Scholar
  181. Wiesmann M, Roelofs M, van der Lugt R, Heerschap A, Kiliaan AJ, Claassen JA (2016) Angiotensin II, hypertension, and angiotensin II receptor antagonism: roles in the behavioural and brain pathology of a mouse model of Alzheimer’s disease. J Cereb Blood Flow Metab 7(7):2396–2413Google Scholar
  182. Wilhelmus MM, Otte-Holler I, van Triel JJ, Veerhuis R, Maat-Schieman ML, Bu G, de Waal RM, Verbeek MM (2007) Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells. Am J Pathol 171:1989–1999PubMedPubMedCentralCrossRefGoogle Scholar
  183. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14:1398–1405PubMedPubMedCentralCrossRefGoogle Scholar
  184. Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S, Kong P, Nelson AR, Sullivan JS, Zhao Z, Meiselman HJ, Wenby RB, Soto J, Abel ED, Makshanoff J, Zuniga E, De Vivo DC, Zlokovic BV (2015) GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18:521–530PubMedPubMedCentralCrossRefGoogle Scholar
  185. Yamaguchi H, Yamazaki T, Lemere CA, Frosch MP, Selkoe DJ (1992) Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer’s disease. An immunoelectron microscopic study. Am J Pathol 141:249–259PubMedPubMedCentralGoogle Scholar
  186. Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC (2011) Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurology 77:48–54PubMedCrossRefGoogle Scholar
  187. Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC (2014) Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology 82:1266–1273PubMedPubMedCentralCrossRefGoogle Scholar
  188. Zaletel M, Strucl M, Pretnar-Oblak J, Zvan B (2005) Age-related changes in the relationship between visual evoked potentials and visually evoked cerebral blood flow velocity response. Funct Neurol 20:115–120PubMedGoogle Scholar
  189. Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T (2010) Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171:852–858PubMedCrossRefGoogle Scholar
  190. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201PubMedCrossRefGoogle Scholar
  191. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738PubMedPubMedCentralGoogle Scholar
  192. Zlokovic BV (2013) Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 70:440–444PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© American Aging Association 2017

Authors and Affiliations

  • Anna Csiszar
    • 1
    • 2
  • Stefano Tarantini
    • 1
    • 2
  • Gábor A. Fülöp
    • 1
    • 2
    • 3
  • Tamas Kiss
    • 1
    • 2
  • M. Noa Valcarcel-Ares
    • 1
    • 2
  • Veronica Galvan
    • 4
  • Zoltan Ungvari
    • 1
    • 2
  • Andriy Yabluchanskiy
    • 1
    • 2
    Email author
  1. 1.Reynolds Oklahoma Center on Aging, Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Division of Clinical PhysiologyFaculty of Medicine, University of DebrecenDebrecenHungary
  4. 4.Department of Cellular and Integrative PhysiologyBarshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San AntonioSan AntonioUSA

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