Pathophysiological Links Among Hypertension and Alzheimer’s Disease

  • Daniela Carnevale
  • Marialuisa Perrotta
  • Giuseppe Lembo
  • Bruno TrimarcoEmail author
Review Article


Genetic Alzheimer’s disease (AD) accounts for only few AD cases and is almost exclusively associated to increased amyloid production in the brain. Instead, the majority of patients is affected with the AD sporadic form with typical alterations of clearance mechanisms of the brain. Most studies use engineered animal models that mimic genetic AD. Since it is emerging the existence of a pathophysiological link between cardiovascular risk factors and AD etiology, the strategy to develop animal models of vascular related AD pathology could be the key toward developing novel successful therapies. On this issue, we have demonstrated that mice that have been chronically subjected to high blood pressure show deposition of amyloid aggregates, the main histological feature of AD, and loss of memory in specific tasks. More importantly, we have identified that the hypertensive challenge increases the expression of the receptor for advanced glycated end products (RAGE), leading to beta-amyloid (Aβ) deposition and learning impairment. Here, we review different murine models of hypertension, induced either pharmacologically or mechanically, leading in the long time to plaque formation in the brain parenchyma and around blood vessels. The major findings obtained till now in this particular experimental setting allow us to suggest that this appears to be a unique possibility to study the pathogenetic mechanisms of sporadic AD triggered by vascular risk factors.


Alzheimer’s disease (AD) Hypertension and cardiovascular risk factors Murine models of vascular-related AD Beta-amyloid (Aβ) deposition and cognitive impairment RAGE, receptor for advanced glycated end products 


  1. 1.
    Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7:476–84.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol. 2002;12:358–70.PubMedGoogle Scholar
  3. 3.
    Skoog I, Gustafson D. Update on hypertension and Alzheimer’s disease. Neurol Res. 2006;28:605–11.CrossRefPubMedGoogle Scholar
  4. 4.
    De la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2003;33:1152–62.CrossRefGoogle Scholar
  5. 5.
    Fotuhi M, Hachinski V, Whitehouse PJ. Changing perspectives regarding late-life dementia. Nat Rev Neurol. 2009;5:649–58.CrossRefPubMedGoogle Scholar
  6. 6.
    Zlokovic BV. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201.CrossRefPubMedGoogle Scholar
  7. 7.
    Hainsworth AH, Markus HS. Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab. 2008;28:1877–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Tsukuda K, Mogi M, Iwanami J, Min LJ, Sakata A, Jing F, Iwai M, Horiuchi M. Cognitive deficit in amyloid-β-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-γ activation. Hypertension. 2009;54:782–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007;117:3393–402.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Girouard H, Park L, Anrathe J, Zhou P, Iadecola C. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2006;27:303–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurol Res. 2004;26:573–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks AI, Kanagala S, Rubio A, Sagare A, et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med. 2005;11:959–65.PubMedGoogle Scholar
  13. 13.
    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008;192:106–13.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007;8:101–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Perlmutter LS, Barron E, Saperia D, Chui H. Association between vascular basement membrane components and the lesions of Alzheimer’s disease. J Neurosci Res. 1991;30:673–81.CrossRefPubMedGoogle Scholar
  17. 17.
    Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Zlokovic BV, Ghiso J, Mackic JB, McComb JG, Weiss MH, Frangione B. Blood–brain barrier transport of circulating Alzheimer’s amyloid β. Biochem Biophys Res Commun. 1993;197:1034–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Mackic JB, Weiss MH, Miao W, Kirkman E, Ghiso J, Calero M, Bading J, Frangione B, Zlokovic BV. Cerebrovascular accumulation and increased blood–brain barrier permeability to circulating Alzheimer’s amyloid β peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem. 1998;70:210–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2:864–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Sterniczuk R, Dyck RH, Laferla FM, Antle MC. Characterization of the 3xTg-AD mouse model of Alzheimer’s disease. Part 1. Circadian changes. Brain Res. 2010;1348:139–48.CrossRefPubMedGoogle Scholar
  24. 24.
    Sterniczuk R, Antle MC, Laferla FM, Dyck RH. Characterization of the 3xTg-AD mouse model of Alzheimer’s disease. Part 2. Behavioral and cognitive changes. Brain Res. 2010;1348:149–55.CrossRefPubMedGoogle Scholar
  25. 25.
    Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kobayashi DT, Chen KS. Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav. 2005;4:173–96.CrossRefPubMedGoogle Scholar
  27. 27.
    Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Prot Natl Acad Sci. 1999;96:3922–7.CrossRefGoogle Scholar
  28. 28.
    Hartman RE, Wozniak DF, Nardi A, Olney JW, Sartorius L, Holtzman DM. Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: apoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology. Exp Neurol. 2001;170:326–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Sullivan PM, Han B, Liu F, Mace BE, Ervin JF, Wu S, Koger D, Paul S, Bales KR. Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging. 2009;32:791–801.CrossRefPubMedGoogle Scholar
  30. 30.
    Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke. 2004;35:2628–31.CrossRefPubMedGoogle Scholar
  31. 31.
    Carnevale C, 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. Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging. 2012;33:205.e19–29.CrossRefGoogle Scholar
  32. 32.
    Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD, Branchi I, Pallante F, Zlokovic B, Yan SS, Lembo G. Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012;60:188–97.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nakamura K, Yamagishi S, Nakamure Y, Takenaka K, Matsui T, Jinnouchi Y, Imaizumi T. Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. Microvasc Res. 2005;70:137–41.CrossRefPubMedGoogle Scholar
  34. 34.
    Bierhaus A, Nawroth PP. Posttranslational modification of lipoproteins-a fatal attraction in metabolic disease? J Alzheimers Dis. 2005;7:315–7.PubMedGoogle Scholar
  35. 35.
    Donahue JE, Flaherty SL, Johanson CE, Duncan JA, Silverberg GD, Miller MC, Tavares R, Yang W, Wu Q, Sabo E, Hovanesian V, Stopa EG. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol. 2006;112:405–15.CrossRefPubMedGoogle Scholar
  36. 36.
    Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res. 2010;106:842–53.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gentile MT, Poulet R, Di Pardo A, Cifelli G, Maffei A, Vecchione C, Passarelli F, Landolfi A, Carullo P, Lembo G. β-Amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009;30:222–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Meenakshisundaram T, Zarcone T, Fritz G, Friedeman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012;122:1377–92.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Daniela Carnevale
    • 1
    • 2
  • Marialuisa Perrotta
    • 1
  • Giuseppe Lembo
    • 1
    • 2
  • Bruno Trimarco
    • 3
    Email author
  1. 1.Department of Angiocardioneurology and Translational MedicineIRCCS NeuromedPozzilliItaly
  2. 2.Department of Molecular MedicineSapienza University of RomeRomeItaly
  3. 3.Division of Cardiology, Department of Advanced Biomedical SciencesFederico II UniversityNaplesItaly

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