Skip to main content

Advertisement

SpringerLink
Log in

Drug Access to the Central Nervous System in Alzheimer’s Disease: Preclinical and Clinical Insights

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by β-amyloid plaques and hyperphosphorylated tau tangles in the brain. Alongside these pathological lesions, there have been multiple reports of physical and biochemical alterations to the blood-brain barrier (BBB) in people with AD, potentially impacting on the ability of systemically-administered drugs to reach the brain parenchyma. Though there has been much research into the identification of these BBB alterations during AD, there are very few studies that have assessed the impact of such BBB changes on the ability of therapeutic agents to traverse the BBB. Due to their increased age-associated risk of chronic disease, most people with AD are prescribed multiple concurrent medications. In people with AD, the altered nature of the BBB could impact upon the disposition and therefore pharmacological effects of a wide range of medicines. This review therefore evaluates the impact of BBB alterations in AD on CNS drug exposure, along with relevant examples of preclinical and clinical studies that address this current issue. This review highlights that the CNS exposure of drugs is likely to differ between people with AD and healthy individuals, warranting further clinical investigations and the consideration to tailor dosing regimens in people with this neurodegenerative disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81(2):741–66.

    CAS  PubMed  Google Scholar 

  2. Hyman BT, Damasio H, Damasio AR, Van Hoesen GW. Alzheimer's Disease. Annu Rev Public Health. 1989;10(1):115–40.

    CAS  PubMed  Google Scholar 

  3. World Alzheimer's Report: Overcoming the stigma of dementia. Alzheimer's disease International.; 2012. Available from: http://www.alz.org/documents_custom/world_report_2012_final.pdf

  4. Alzheimer's disease fact-sheet. National Institute on Aging.; 2011 Available from: http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet

  5. Therapeutic Goods Administration. Department of Health, Australian Government.; 2011 Available from: http://www.tga.gov.au/hp/information-medicines-pi.htm#.U46isfmSySp.

  6. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380(9836):37–43.

    PubMed  Google Scholar 

  7. Britt HC, Harrison CM, Miller GC, Knox SA. Prevalence and patterns of multimorbidity in Australia. Med J Aust. 2008;189(2):72–7.

    PubMed  Google Scholar 

  8. Salive ME. Multimorbidity in older adults. Epidemiol Rev. 2013;35(1):75–83.

    Google Scholar 

  9. Andersen F, Viitanen M, Halvorsen D, Straume B, Engstad T. Co-morbidity and drug treatment in Alzheimer's disease. A cross sectional study of participants in the Dementia Study in Northern Norway. BMC Geriatr. 2011;11(1):58.

    PubMed Central  PubMed  Google Scholar 

  10. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57(2):173–85.

    CAS  PubMed  Google Scholar 

  11. Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1(5):409–17.

    CAS  PubMed  Google Scholar 

  12. Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K. Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci. 1988;529(1):21–30.

    CAS  PubMed  Google Scholar 

  13. Sedlakova R, Shivers RR, Del Maestro RF. Ultrastructure of the blood-brain barrier in the rabbit. J Submicrosc Cytol Pathol. 1999;31(1):149–61.

    CAS  PubMed  Google Scholar 

  14. Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell Mol Neurobiol. 2000;20(1):57–76.

    CAS  PubMed  Google Scholar 

  15. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. 2007;12(1–2):54–61.

    CAS  PubMed  Google Scholar 

  16. Bendayan R, Lee G, Bendayan M. Functional expression and localization of P-glycoprotein at the blood-brain barrier. Microsc Res Tech. 2002;57(5):365–80.

    CAS  PubMed  Google Scholar 

  17. Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann J-M. Expression, up-regulation, and transport activity of the multidrug-resistance protein abcg2 at the mouse blood-brain barrier. Cancer Res. 2004;64(9):3296–301.

    CAS  PubMed  Google Scholar 

  18. Dallas S, Miller DS, Bendayan R. Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol Rev. 2006;58(2):140–61.

    CAS  PubMed  Google Scholar 

  19. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.

  20. Löscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 2005;76(1):22–76.

    PubMed  Google Scholar 

  21. Nies AT, Jedlitschky G, König J, Herold-Mende C, Steiner HH, Schmitt HP, et al. Expression and immunolocalization of the multidrug resistance proteins, MRP1–MRP6 (ABCC1–ABCC6), in human brain. Neuroscience. 2004;129(2):349–60.

    CAS  PubMed  Google Scholar 

  22. Cattelotte J, Andre P, Ouellet M, Bourasset F, Scherrmann JM, Cisternino S. In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain. J Cereb Blood Flow Metab. 2008;28(8):1449–59.

    PubMed  Google Scholar 

  23. Kido Y, Tamai I, Okamoto M, Suzuki F, Tsuji A. Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies. Pharm Res. 2000;17(1):55–62.

    CAS  PubMed  Google Scholar 

  24. Kido Y, Tamai I, Uchino H, Suzuki F, Sai Y, Tsuji A. Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier. J Pharm Pharmacol. 2001;53(4):497–503.

    CAS  PubMed  Google Scholar 

  25. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood–brain barrier. Neurobiol Dis. 2010;37(1):13–25.

    CAS  PubMed  Google Scholar 

  26. Upton RN. Cerebral uptake of drugs in humans. Clin Exp Pharmacol Physiol. 2007;34(8):695–701.

    CAS  PubMed  Google Scholar 

  27. Upton RN, Ludbrook GL, Grant C, Doolette DJ. The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep. Anesthesiology. 2000;93(4):1085–94.

    CAS  PubMed  Google Scholar 

  28. Zwolinski BJ, Eyring H, Reese CE. Diffusion and membrane permeability. J Phys Chem. 1948;53(9):1426–53.

    Google Scholar 

  29. Doraiswamy PM, Leon J, Cummings JL, Marin D, Neumann PJ. Prevalence and impact of medical comorbidity in Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2002;57(3):M173–7.

    PubMed  Google Scholar 

  30. McCarron M, Gill M, McCallion P, Begley C. Health co-morbidities in ageing persons with Down syndrome and Alzheimer's dementia. J Intellect Disabil Res. 2005;49(7):560–6.

    CAS  PubMed  Google Scholar 

  31. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355(15):1525–38.

    CAS  PubMed  Google Scholar 

  32. Nobili A, Pasina L, Trevisan S, Riva E, Lucca U, Tettamanti M, et al. Use and misuse of antipsychotic drugs in patients with dementia in Alzheimer special care units. Int Clin Psychopharmacol. 2009;24(2):97–104.

    PubMed  Google Scholar 

  33. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934–43.

    CAS  PubMed  Google Scholar 

  34. Montastruc F, Gardette V, Cantet C, Piau A, Lapeyre-Mestre M, Vellas B, et al. Potentially inappropriate medication use among patients with Alzheimer disease in the REAL.FR cohort: be aware of atropinic and benzodiazepine drugs! Eur J Clin Pharmacol. 2013;69(8):1589–97.

    PubMed  Google Scholar 

  35. Gnjidic D, Cumming RG, Le Couteur DG, Handelsman DJ, Naganathan V, Abernethy DR, et al. Drug burden index and physical function in older Australian men. Br J Clin Pharmacol. 2009;68(1):97–105.

    PubMed Central  PubMed  Google Scholar 

  36. Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, et al. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model. J Clin Invest. 2005;115(11):3285–90.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Claudio L. Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's disease patients. Acta Neuropathol. 1996;91(1):6–14.

    CAS  PubMed  Google Scholar 

  38. Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, et al. ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Aβ1–40 peptides. J Neurosci. 2009;29(17):5463–75.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, et al. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging. 2007;28(7):977–86.

    CAS  PubMed  Google Scholar 

  40. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.

    CAS  PubMed  Google Scholar 

  41. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.

    CAS  PubMed  Google Scholar 

  42. Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 1998;8(11):447–53.

    CAS  PubMed  Google Scholar 

  43. Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–800.

    PubMed  Google Scholar 

  44. Capetillo-Zarate E, Gracia L, Tampellini D, Gouras GK. Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer’s disease. Neurodegener Dis. 2012;10(1–4):56–9.

    CAS  PubMed  Google Scholar 

  45. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, et al. Intraneuronal Aβ42 accumulation in human brain. Am J Pathol. 2000;156(1):15–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Nerelius C, Johansson J, Sandegren A. Amyloid β-peptide aggregation. What does it result in and how can it be prevented? Front Biosci. 2009;14:1716–29.

    CAS  Google Scholar 

  47. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer's disease. Nat Rev Neurosci. 2007;8(7):499–509.

    CAS  PubMed  Google Scholar 

  48. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, et al. Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci. 2008;28(45):11650–61.

    CAS  PubMed  Google Scholar 

  49. Pike CJ, Cummings BJ, Cotman CW. Early association of reactive astrocytes with senile plaques in Alzheimer's disease. Exp Neurol. 1995;132(2):172–9.

    CAS  PubMed  Google Scholar 

  50. Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol. 2001;158(4):1345–54.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM. Direct evidence of oxidative injury produced by the Alzheimer's β-Amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol. 1995;131(2):193–202.

    CAS  PubMed  Google Scholar 

  52. Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer's disease. Acta Neuropathol. 2008;115(6):599–609.

    CAS  PubMed  Google Scholar 

  53. Vinters HV, Secor DL, Read SL, Frazee JG, Tomiyasu U, Stanley TM, et al. Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct Pathol. 1994;18(3):333–48.

    CAS  PubMed  Google Scholar 

  54. Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke. 2004;35(11 Suppl 1):2616–9.

    PubMed  Google Scholar 

  55. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62(12):1287–301.

    PubMed  Google Scholar 

  56. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai L-H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999;402(6762):615–22.

    CAS  PubMed  Google Scholar 

  58. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83(13):4913–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001;98(12):6923–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging. 2003;24(8):1079–85.

    CAS  PubMed  Google Scholar 

  61. Jaworski T, Lechat B, Demedts D, Gielis L, Devijver H, Borghgraef P, et al. Dendritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration. Am J Pathol. 2011;179(4):2001–15.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Pimentel-Coelho PM, Rivest S. The early contribution of cerebrovascular factors to the pathogenesis of Alzheimer’s disease. Eur J Neurosci. 2012;35(12):1917–37.

    PubMed  Google Scholar 

  63. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke. 2004;35(11 suppl 1):2620–2.

    PubMed  Google Scholar 

  64. de La Torre J. Alzheimer's disease is a vasocognopathy: a new term to describe its nature. Neurol Res. 2004;26(5):517–24.

    PubMed  Google Scholar 

  65. de la Torre JC. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3(3):184–90.

    PubMed  Google Scholar 

  66. Kalaria RN. The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease. Ann N Y Acad Sci. 1999;893(1):113–25.

    CAS  PubMed  Google Scholar 

  67. Bailey T, Rivara C, Rocher A, Hof P. The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease. Neurol Res. 2004;26(5):573–8.

    PubMed  Google Scholar 

  68. Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol. 2001;64(6):575–611.

    CAS  PubMed  Google Scholar 

  69. Alsop DC, Detre JA, Grossman M. Assessment of cerebral blood flow in Alzheimer's disease by spin-labeled magnetic resonance imaging. Ann Neurol. 2000;47(1):93–100.

    CAS  PubMed  Google Scholar 

  70. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis. 2002;9(1):61–8.

    CAS  PubMed  Google Scholar 

  71. Jagust WJ, Seab JP, Huesman RH, Valk PE, Mathis CA, Reed BR, et al. Diminished glucose transport in Alzheimer's disease: dynamic PET studies. J Cereb Blood Flow Metab. 1991;11(2):323–30.

    CAS  PubMed  Google Scholar 

  72. Nicholson RM, Kusne Y, Nowak LA, LaFerla FM, Reiman EM, Valla J. Regional cerebral glucose uptake in the 3 × TG model of Alzheimer's disease highlights common regional vulnerability across AD mouse models. Brain Res. 2010;1347:179–85.

    CAS  PubMed  Google Scholar 

  73. Piert M, Koeppe RA, Giordani B, Berent S, Kuhl DE. Diminished glucose transport and phosphorylation in Alzheimer's disease determined by dynamic FDG-PET. J Nucl Med. 1996;37(2):201–8.

    CAS  PubMed  Google Scholar 

  74. Maalikjy Akkawi N, Borroni B, Agosti C, Pezzini A, Magoni M, Rozzini L, et al. Volume reduction in cerebral blood flow in patients with Alzheimer’s disease: a sonographic study. Dement Geriatr Cogn Disord. 2003;16(3):163–9.

    CAS  PubMed  Google Scholar 

  75. Du AT, Jahng GH, Hayasaka S, Kramer JH, Rosen HJ, Gorno-Tempini ML, et al. Hypoperfusion in frontotemporal dementia and Alzheimer disease by arterial spin labeling MRI. Neurology. 2006;67(7):1215–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Bartenstein P, Minoshima S, Hirsch C, Buch K, Willoch F, Mösch D, et al. Quantitative assessment of cerebral blood flow in patients with Alzheimer's disease by SPECT. J Nucl Med. 1997;38(7):1095–101.

    CAS  PubMed  Google Scholar 

  77. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 2009;118(1):103–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc Natl Acad Sci U S A. 2007;104(3):823–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Barbelivien A, Bertrand N, Besret L, Beley A, MacKenzie ET, Dauphin F. Neurochemical stimulation of the rat substantia innominata increases cerebral blood flow (but not glucose use) through the parallel activation of cholinergic and non-cholinergic pathways. Brain Res. 1999;840(1–2):115–24.

    CAS  PubMed  Google Scholar 

  80. Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimura J, Yonekura Y, et al. Altered cerebral energy metabolism in Alzheimer's disease: a PET study. J Nucl Med. 1994;35(1):1–6.

    CAS  PubMed  Google Scholar 

  81. De Jong GI, Farkas E, Stienstra CM, Plass JRM, Keijser JN, de la Torre JC, et al. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience. 1999;91(1):203–10.

    PubMed  Google Scholar 

  82. de la Torre JC. Cerebral hypoperfusion, capillary degeneration, and development of Alzheimer disease. Alzheimer Dis Assoc Disord. 2000;14(1):S72–81.

    PubMed  Google Scholar 

  83. Holland CM, Smith EE, Csapo I, Gurol ME, Brylka DA, Killiany RJ, et al. Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke. 2008;39(4):1127–33.

    PubMed Central  PubMed  Google Scholar 

  84. Okamoto Y, Yamamoto T, Kalaria R, Senzaki H, Maki T, Hase Y, et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 2012;123(3):381–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Wang X, Xing A, Xu C, Cai Q, Liu H, Li L. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J Alzheimer's Dis. 2010;21(3):813–22.

    CAS  Google Scholar 

  86. Shah K, DeSilva S, Abbruscato T. The role of glucose transporters in brain disease: diabetes and Alzheimer's disease. Int J Mol Sci. 2012;13(10):12629–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Kalaria RN, Harik SI. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer Disease. J Neurochem. 1989;53(4):1083–8.

    CAS  PubMed  Google Scholar 

  88. Reiman EM, Uecker A, Gonzalez-Lima F, Minear D, Chen K, Callaway NL, et al. Tracking Alzheimer's disease in transgenic mice using fluorodeoxyglucose autoradiography. Neuroreport. 2000;11(5):987–91.

    CAS  PubMed  Google Scholar 

  89. Hoyer S, Nitsch R, Oesterreich K. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: A cross-sectional comparison against advanced late-onset and incipient early-onset cases. J Neural Transm Gen Sect. 1991;3(1):1–14.

    CAS  Google Scholar 

  90. Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol. 1994;35(5):546–51.

    CAS  PubMed  Google Scholar 

  91. Mooradian AD, Chung HC, Shah GN. GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging. 1997;18(5):469–74.

    CAS  PubMed  Google Scholar 

  92. Harr SD, Simonian NA, Hyman BT. Functional alterations in Alzheimer's disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathol Exp Neurol. 1995;54(1):38–41.

    CAS  PubMed  Google Scholar 

  93. Serrano ID, Ribeiro MM, Castanho MA. A focus on glucose-mediated drug delivery to the central nervous system. Mini-Rev Med Chem. 2012;12(4):301–12.

    CAS  PubMed  Google Scholar 

  94. Storr T, Scott LE, Bowen ML, Green DE, Thompson KH, Schugar HJ, et al. Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy. Dalton Trans. 2009;(16):3034–43

  95. Chen Q, Gong T, Liu J, Wang X, Fu H, Zhang Z. Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery. J Drug Target. 2009;17(4):318–28.

    CAS  PubMed  Google Scholar 

  96. Xiuli G, Meiyu G, Guanhua D. Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem Genet. 2005;43(3–4):175–87.

    Google Scholar 

  97. Egleton RD, Mitchell SA, Huber JD, Janders J, Stropova D, Polt R, et al. Improved bioavailability to the brain of glycosylated Met-enkephalin analogs. Brain Res. 2000;881(1):37–46.

    CAS  PubMed  Google Scholar 

  98. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–13.

    CAS  PubMed  Google Scholar 

  99. Miller MC, Tavares R, Johanson CE, Hovanesian V, Donahue JE, Gonzalez L, et al. Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease. Brain Res. 2008;1230:273–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Jeynes B, Provias J. Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Curr Alzheimer Res. 2008;5(5):432–7.

    CAS  PubMed  Google Scholar 

  101. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature. 1996;382(6593):685–91.

    CAS  PubMed  Google Scholar 

  102. Buee L, Hof P, Delacourte A. Brain microvascular changes in Alzheimer's disease and other dementias. Ann N Y Acad Sci. 1997;826(1):7–24.

    CAS  PubMed  Google Scholar 

  103. Miyakawa T, Uehara Y, Desaki J, Kimura T, Kuramoto R. Morphological changes of microvessels in the brain with Alzheimer's disease. Psychiatry Clin Neurosci. 1988;42(4):819–24.

    CAS  Google Scholar 

  104. Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med. 2005;11(9):959–65.

    CAS  PubMed  Google Scholar 

  105. Higuchi Y, Miyakawa T, Shimoji A, Katsuragi S. Ultrastructural changes of blood vessels in the cerebral cortex in Alzheimer's disease. Jpn J Psychiatry Neurol. 1987;41(2):283–90.

    CAS  PubMed  Google Scholar 

  106. Stewart PA, Hayakawa K, Akers MA, Vinters HV. A morphometric study of the blood-brain barrier in Alzheimer's disease. Lab Invest. 1992;67(6):734–42.

    CAS  PubMed  Google Scholar 

  107. Kalaria RN, Pax AB. Increased collagen content of cerebral microvessels in Alzheimer's disease. Brain Res. 1995;705(1–2):349–52.

    CAS  PubMed  Google Scholar 

  108. Mehta DC, Short JL, Nicolazzo JA. Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer’s disease. Pharm Res. 2013;30(11):2868–79.

    CAS  PubMed  Google Scholar 

  109. Mehta DC, Short JL, Nicolazzo JA. Reduced CNS exposure of memantine in a triple transgenic mouse model of Alzheimer's disease assessed using a novel LC–MS technique. J Pharm Biomed Anal. 2013;85:198–206.

    CAS  PubMed  Google Scholar 

  110. Shimohama S, Taniguchi T, Fujiwara M, Kameyama M. Changes in β-adrenergic receptor subtypes in Alzheimer-type dementia. J Neurochem. 1987;48(4):1215–21.

    CAS  PubMed  Google Scholar 

  111. Kalaria RN, Andorn AC, Tabaton M, Whitehouse PJ, Harik SI, Unnerstall JR. Adrenergic receptors in aging and Alzheimer's disease: increased β2-receptors in prefrontal cortex and hippocampus. J Neurochem. 1989;53(6):1772–81.

    CAS  PubMed  Google Scholar 

  112. Limon A, Reyes-Ruiz JM, Miledi R. Loss of functional GABAA receptors in the Alzheimer diseased brain. Proc Natl Acad Sci U S A. 2012;109(25):10071–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol Res. 1993;15:146–53.

    PubMed  Google Scholar 

  114. Gnjidic D, Hilmer SN, Hartikainen S, Tolppanen A-M, Taipale H, Koponen M, et al. Impact of high risk drug use on hospitalization and mortality in older people with and without Alzheimer's disease: a national population cohort study. PLoS One. 2014;9(1):e83224.

    PubMed Central  PubMed  Google Scholar 

  115. Cutler RWP, Deuel RK, Barlow CF. Albumin exchange between plasma and cerebrospinal fluid. Arch Neurol. 1967;17(3):261–70.

    CAS  PubMed  Google Scholar 

  116. Tibbling G, Link H, Öhman S. Principles of albumin and IgG analyses in neurological disorders I Establishment of reference values. Scand J Clin Lab Invest. 1977;37(5):385–90.

    CAS  PubMed  Google Scholar 

  117. Blennow K, Fredman P, Wallin A, Gottfries CG, Karlsson I, Långstrom G, et al. Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol. 1993;33(2):129–33.

    CAS  PubMed  Google Scholar 

  118. Hampel H, Müller-Spahn F, Berger C, Haberl A, et al. Evidence of blood-cerebrospinal fluid-barrier impairment in a subgroup of patients with dementia of the Alzheimer type and major depression: A possible indicator for immunoactivation. Dementia. 1995;6(6):348–54.

    CAS  PubMed  Google Scholar 

  119. Wada H. Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio. Intern Med. 1998;37:509–13.

    CAS  PubMed  Google Scholar 

  120. Algotsson A, Winblad B. The integrity of the blood–brain barrier in Alzheimer’s disease. Acta Neurol Scand. 2007;115(6):403–8.

    CAS  PubMed  Google Scholar 

  121. Elovaara I, Palo J, Erkinjuntti T, Sulkava R. Serum and cerebrospinal fluid proteins and the blood-brain barrier in Alzheimer's disease and multi-infarct dementia. Eur Neurol. 1987;26(4):229–34.

    CAS  PubMed  Google Scholar 

  122. Frölich L, Kornhuber J, Ihl R, Fritze J, Maurer K, Riederer P. Integrity of the blood-CSF barrier in dementia of Alzheimer type: CSF/serum ratios of albumin and IgG. Eur Arch Psychiatry Clin Neurosci. 1991;240(6):363–6.

    PubMed  Google Scholar 

  123. Kay AD, May C, Papadopoulos NM, Costello R, Atack JR, Luxenberg JS, et al. CSF and serum concentrations of albumin and IgG in Alzheimer's disease. Neurobiol Aging. 1987;8(1):21–5.

    CAS  PubMed  Google Scholar 

  124. Alafuzoff I, Adolfsson R, Grundke-Iqbal I, Winblad B. Blood-brain barrier in Alzheimer dementia and in non-demented elderly. Acta Neuropathol. 1987;73(2):160–6.

    CAS  PubMed  Google Scholar 

  125. Mecocci P, Parnetti L, Reboldi GP, Santucci C, Gaiti A, Ferri C, et al. Blood-brain-barrier in a geriatric population: barrier function in degenerative and vascular dementias. Acta Neurol Scand. 1991;84(3):210–3.

    CAS  PubMed  Google Scholar 

  126. Leonardi A, Gandolfo C, Caponnetto C, Arata L, Vecchia R. The integrity of the blood-brain barrier in Alzheimer's type and multi-infarct dementia evaluated by the study of albumin and IgG in serum and cerebrospinal fluid. J Neurol Sci. 1985;67(2):253–61.

    CAS  PubMed  Google Scholar 

  127. Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD, Bronte–Stewart H, et al. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology. 2001;57(10):1763–6.

    CAS  PubMed  Google Scholar 

  128. Johanson C, Duncan J, Stopa E, Baird A. Enhanced prospects for drug delivery and brain targeting by the choroid plexus–CSF route. Pharm Res. 2005;22(7):1011–37.

    CAS  PubMed  Google Scholar 

  129. Rozemuller JM, Eikelenboom P, Kamphorst W, Stam FC. Lack of evidence for dysfunction of the blood-brain barrier in Alzhiemer's disease: an immunohistochemical study. Neurobiol Aging. 1988;9:383–91.

    CAS  PubMed  Google Scholar 

  130. Caserta MT, Caccioppo D, Lapin GD, Ragin A, Groothuis DR. Blood-brain barrier integrity in Alzheimer's disease patients and elderly control subjects. J Neuropsychiatry Clin Neurosci. 1998;10(1):78–84.

    CAS  PubMed  Google Scholar 

  131. Starr JM, Farrall AJ, Armitage P, McGurn B, Wardlaw J. Blood–brain barrier permeability in Alzheimer's disease: a case–control MRI study. Psychiatry Res. 2009;171(3):232–41.

    CAS  PubMed  Google Scholar 

  132. Schlageter NL, Carson RE, Rapoport IS. Examination of blood-brain barrier permeability in dementia of the Alzheimer type with [68Ga]EDTA and positron emission tomography. J Cereb Blood Flow Metab. 1987;7(1):1–8.

    CAS  PubMed  Google Scholar 

  133. Gonzalez-Velasquez FJ, Kotarek JA, Moss MA. Soluble aggregates of the amyloid-β protein selectively stimulate permeability in human brain microvascular endothelial monolayers. J Neurochem. 2008;107(2):466–77.

    CAS  PubMed  Google Scholar 

  134. Tai LM, Holloway KA, Male DK, Loughlin AJ, Romero IA. Amyloid-β-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation. J Cell Mol Med. 2010;14(5):1101–12.

    CAS  PubMed  Google Scholar 

  135. Marco S, Skaper SD. Amyloid β -peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells. Neurosci Lett. 2006;401:219–24.

    CAS  PubMed  Google Scholar 

  136. Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP. Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett. 2001;304(1–2):102–6.

    CAS  PubMed  Google Scholar 

  137. Jancsó G, Domoki F, Sántha P, Varga J, Fischer J, Orosz K, et al. β-Amyloid (1–42) peptide impairs blood-brain barrier function after intracarotid infusion in rats. Neurosci Lett. 1998;253(2):139–41.

    PubMed  Google Scholar 

  138. Farkas IG, Czigner A, Farkas E, Dobó E, Soós K, Penke B, et al. β-amyloid peptide-induced blood-brain barrier disruption facilitates T-cell entry into the rat brain. Acta Histochem. 2003;105(2):115–25.

    PubMed  Google Scholar 

  139. Woodruff-Pak DS. Animal models of Alzheimer's disease: therapeutic implications. J Alzheimers Dis. 2008;15(4):507–21.

    CAS  PubMed  Google Scholar 

  140. Yamada K, Nabeshima T. Animal models of Alzheimer's disease and evaluation of anti-dementia drugs. Pharmacol Ther. 2000;88(2):93–113.

    CAS  PubMed  Google Scholar 

  141. Pelegrí C, Canudas AM, del Valle J, Casadesus G, Smith MA, Camins A, et al. Increased permeability of blood–brain barrier on the hippocampus of a murine model of senescence. Mech Ageing Dev. 2007;128(9):522–8.

    PubMed  Google Scholar 

  142. Takechi R, Galloway S, Pallebage-Gamarallage MM, Mamo JC. Chylomicron amyloid-β in the aetiology of Alzheimer's disease. Atheroscler Suppl. 2008;9(2):19–25.

    CAS  PubMed  Google Scholar 

  143. Ujiie M, Dickstein DL, Carlow DA, Jefferies WA. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation. 2003;10(6):463–70.

    CAS  PubMed  Google Scholar 

  144. Ueno M, Akiguchi I, Hosokawa M, Shinnou M, Sakamoto H, Takemura M, et al. Age-related changes in barrier function in mouse brain: II Accumulation of serum albumin in the olfactory bulb of SAM mice increased with aging. Arch Gerontol Geriatr. 1997;25(3):321–31.

    CAS  PubMed  Google Scholar 

  145. Ueno M, Akiguchi I, Yagi H, Naiki H, Fujibayashi Y, Kimura J, et al. Age-related changes in barrier function in mouse brain I. Accelerated age-related increase of brain transfer of serum albumin in accelerated senescence prone SAM-P/8 mice with deficits in learning and memory. Arch Gerontol Geriatr. 1993;16(3):233–48.

    CAS  PubMed  Google Scholar 

  146. Bourasset F, Ouellet M, Tremblay C, Julien C, Do TM, Oddo S, et al. Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease. Neuropharmacology. 2009;56(4):808–13.

    CAS  PubMed  Google Scholar 

  147. Cheng Z, Zhang J, Liu H, Li Y, Zhao Y, Yang E. Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis- and Alzheimer's disease-related animal models despite reported blood-brain barrier disruption. Drug Metab Dispos. 2010;38(8):1355–61.

    CAS  PubMed  Google Scholar 

  148. Banks WA, Farr SA, Morley JE. Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse. J Gerontol A Biol Sci Med Sci. 2000;55(12):601–6.

    Google Scholar 

  149. Poduslo JF, Curran GL, Wengenack TM, Malester B, Duff K. Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2001;8(4):555–67.

    CAS  PubMed  Google Scholar 

  150. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005;28(4):202–8.

    CAS  PubMed  Google Scholar 

  151. Abuznait AH, Kaddoumi A. Role of ABC transporters in the pathogenesis of Alzheimer's disease. ACS Chem Neurosci. 2012;11:820–31.

    Google Scholar 

  152. Wolf A, Bauer B, Hartz AMS. ABC transporters and the Alzheimer’s disease enigma. Front Psychiatry. 2012;3:54.

    PubMed Central  CAS  PubMed  Google Scholar 

  153. Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier. Stroke. 2004;35(11 Suppl 1):2628–31.

    CAS  PubMed  Google Scholar 

  154. Herz J, The LDL. Receptor Gene Family: (Un)Expected Signal Transducers in the Brain. Neuron. 2001;29(3):571–81.

    CAS  PubMed  Google Scholar 

  155. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron. 2004;43(3):333–44.

    CAS  PubMed  Google Scholar 

  156. Deane R, Sagare A, Zlokovic BV. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer's disease. Curr Pharm Des. 2008;14(16):1601–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  157. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27(5):909–18.

    PubMed Central  CAS  PubMed  Google Scholar 

  158. Jaeger LB, Dohgu S, Hwang MC, Farr SA, Murphy MP, Fleegal-DeMotta MA, et al. Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-β protein, and impairs cognition. J Alzheimers Dis. 2009;17(3):553–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  159. Donahue JE, Flaherty SL, Johanson CE, Duncan JAR, Silverberg GD, Miller MC, et al. RAGE, LRP-1, and amyloid-β protein in Alzheimer's disease. Acta Neuropathol. 2006;112(4):405–15.

    CAS  PubMed  Google Scholar 

  160. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer's amyloid-β1–40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106(12):1489–99.

    PubMed Central  CAS  PubMed  Google Scholar 

  161. Erickson M, Hartvigson P, Morofuji Y, Owen J, Butterfield D, Banks W. Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J Neuroinflammation. 2012;9(1):150.

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Erickson MA, Hansen K, Banks WA. Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood–brain barrier: protection by the antioxidant N-acetylcysteine. Brain Behav Immun. 2012;26(7):1085–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Bertrand Y, Currie J-C, Demeule M, Régina A, Ché C, Abulrob A, et al. Transport characteristics of a novel peptide platform for CNS therapeutics. J Cell Mol Med. 2010;14(12):2827–39.

    CAS  PubMed  Google Scholar 

  164. Bertrand Y, Currie JC, Poirier J, Demeule M, Abulrob A, Fatehi D, et al. Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1. Br J Cancer. 2011;105(11):1697–707.

    PubMed Central  CAS  PubMed  Google Scholar 

  165. Proulx DP, Rouleau P, Paré I, Vallières-Noël MM, Bazin R. Interaction between intravenous immunoglobulin (IVIg) and the low-density lipoprotein receptor-related protein 1: a role for transcytosis across the blood brain barrier? J Neuroimmunol. 2012;251(1–2):39–44.

    CAS  PubMed  Google Scholar 

  166. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97(7):889–901.

    CAS  PubMed  Google Scholar 

  167. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995;270(43):25752–61.

    CAS  PubMed  Google Scholar 

  168. Silverberg GD, Miller MC, Messier AA, Majmudar S, Machan JT, Donahue JE, et al. Amyloid deposition and influx transporter expression at the blood-brain barrier increase in normal aging. J Neuropathol Exp Neurol. 2010;69(1):98–108.

    CAS  PubMed  Google Scholar 

  169. Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, et al. Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiol Aging. 2011;32(5):763–77.

    CAS  PubMed  Google Scholar 

  170. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455(1):152–62.

    CAS  PubMed  Google Scholar 

  171. Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science. 1983;221:1285–8.

    CAS  PubMed  Google Scholar 

  172. Gros P, Croop J, Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell. 1986;47(3):371–80.

    CAS  PubMed  Google Scholar 

  173. Chin JE, Soffir R, Noonan KE, Choi K, Roninson IB. Structure and expression of the human MDR (P-glycoprotein) gene family. Mol Cell Biol. 1989;9(9):3808–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  174. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84(21):7735–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Lee G, Bendayan R. Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res. 2004;21(8):1313–30.

    CAS  PubMed  Google Scholar 

  176. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A. 1989;86(2):695–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Beaulieu E, Demeule M, Ghitescu L, Béliveau R. P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem J. 1997;326(2):539–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Bendayan R, Ronaldson PT, Gingras D, Bendayan M. In situ localization of P-glycoprotein (ABCB1) in human and rat brain. J Histochem Cytochem. 2006;54(10):1159–67.

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev. 1999;36(2–3):179–94.

    CAS  PubMed  Google Scholar 

  180. Bihorel S, Camenisch G, Lemaire M, Scherrmann J-M. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res. 2007;24(9):1720–8.

    CAS  PubMed  Google Scholar 

  181. Schinkel AH, Smit JJM, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491–502.

    CAS  PubMed  Google Scholar 

  182. Wang T, Agarwal S, Elmquist WF. Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J Pharmacol Exp Ther. 2012;341(2):386–95.

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Kim W, Benet L. P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res. 2004;21(7):1284–93.

    CAS  PubMed  Google Scholar 

  184. Watchko JF, Daood MJ, Hansen TWR. Brain bilirubin content is increased in P-glycoprotein-deficient transgenic null mutant mice. Pediatr Res. 1998;44(5):763–6.

    CAS  PubMed  Google Scholar 

  185. McRae MP, Brouwer KLR, Kashuba ADM. Cytokine regulation of P-glycoprotein. Drug Metab Rev. 2003;35(1):19–33.

    CAS  PubMed  Google Scholar 

  186. Kuhnke D, Jedlitschky G, Grube M, Krohn M, Jucker M, Mosyagin I, et al. MDR1-P-glycoprotein (ABCB1) mediates transport of Alzheimer's amyloid-β peptides–implications for the mechanisms of Aβ clearance at the blood-brain barrier. Brain Pathol. 2007;17(4):347–53.

    CAS  PubMed  Google Scholar 

  187. Lam FC, Liu R, Lu P, Shapiro AB, Renoir JM, Sharom FJ, et al. β-Amyloid efflux mediated by P-glycoprotein. J Neurochem. 2001;76(4):1121–8.

    CAS  PubMed  Google Scholar 

  188. Hartz AM, Miller DS, Bauer B. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-β in a mouse model of Alzheimer's disease. Mol Pharmacol. 2010;77:715–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  189. Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, et al. Deposition of Alzheimer's β-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002;12(7):535–41.

    CAS  PubMed  Google Scholar 

  190. Jeynes B, Provias J. An investigation into the role of P-glycoprotein in Alzheimer's disease lesion pathogenesis. Neurosci Lett. 2011;487(3):389–93.

    CAS  PubMed  Google Scholar 

  191. Vogelgesang S, Warzok RW, Cascorbi I, Kunert-Keil C, Schroeder E, Kroemer HK, et al. The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimers disease. Curr Alzheimer Res. 2004;1(2):121–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  192. Wijesuriya HC, Bullock JY, Faull RLM, Hladky SB, Barrand MA. ABC efflux transporters in brain vasculature of Alzheimer's subjects. Brain Res. 2010;1358:228–38.

    CAS  PubMed  Google Scholar 

  193. Brenn A, Grube M, Peters M, Fischer A, Jedlitschky G, Kroemer HK, et al. Beta-amyloid downregulates MDR1-P-glycoprotein (Abcb1) expression at the blood-brain barrier in mice. Int J Alzheimers Dis. 2011;2011:690121.

    PubMed Central  PubMed  Google Scholar 

  194. Kania KD, Wijesuriya HC, Hladky SB, Barrand MA. Beta amyloid effects on expression of multidrug efflux transporters in brain endothelial cells. Brain Res. 2011;1418:1–11.

    CAS  PubMed  Google Scholar 

  195. Bartels AL, Kortekaas R, Bart J, Willemsen ATM, de Klerk OL, de Vries JJ, et al. Blood–brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration. Neurobiol Aging. 2009;30(11):1818–24.

    CAS  PubMed  Google Scholar 

  196. van Assema DM, Lubberink M, Rizzu P, van Swieten J, Schuit R, Eriksson J, et al. Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene. EJNMMI Res. 2012;2(1):57.

    PubMed Central  PubMed  Google Scholar 

  197. Deo AK, Borson S, Link JM, Domino K, Eary JF, Ke B, et al. Activity of P-glycoprotein, a β-amyloid transporter at the blood–brain barrier, is compromised in patients with mild Alzheimer's disease. J Nucl Med. 2014;55(7):1106–11.

    CAS  PubMed  Google Scholar 

  198. van Assema DM, Lubberink M, Bauer M, van der Flier WM, Schuit RC, Windhorst AD, et al. Blood–brain barrier P-glycoprotein function in Alzheimer's disease. Brain. 2012;135(1):181–9.

    PubMed  Google Scholar 

  199. Moore AR, O'Keefee ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;15(1):15–28.

    CAS  PubMed  Google Scholar 

  200. Chang C-B, Chan D-C. Comparison of published explicit criteria for potentially inappropriate medications in older adults. Drugs Aging. 2010;27(12):947–57.

    PubMed  Google Scholar 

  201. Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics. 2002;2(3):191–96.

    CAS  Google Scholar 

  202. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998;95(26):15665–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  203. Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg ACLM, Schinkel AH, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 2001;61(8):3458–64.

    CAS  PubMed  Google Scholar 

  204. Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD. Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun. 2004;326(1):181–7.

    Google Scholar 

  205. Eisenblätter T, Galla H-J. A new multidrug resistance protein at the blood–brain barrier. Biochem Biophys Res Commun. 2002;293(4):1273–8.

    PubMed  Google Scholar 

  206. Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB. Expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J. 2003;17(14):2085–7.

    PubMed  Google Scholar 

  207. Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010;334(1):147–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  208. Bihorel S, Camenisch G, Lemaire M, Scherrmann J-M. Influence of breast cancer resistance protein (Abcg2) and P-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood–brain barrier. J Neurochem. 2007;102(6):1749–57.

    CAS  PubMed  Google Scholar 

  209. de Vries NA, Zhao J, Kroon E, Buckle T, Beijnen JH, van Tellingen O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res. 2007;13(21):6440–9.

    PubMed  Google Scholar 

  210. Tai LM, Loughlin AJ, Male DK, Romero IA. P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-β. J Cereb Blood Flow Metab. 2009;29(6):1079–83.

    CAS  PubMed  Google Scholar 

  211. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, et al. Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest. 2011;121(10):3924–31.

    PubMed Central  CAS  PubMed  Google Scholar 

  212. Carrano A, Snkhchyan H, Kooij G, van der Pol S, van Horssen J, Veerhuis R, et al. ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy. Neurobiol Aging. 2014;35(3):565–75.

    CAS  PubMed  Google Scholar 

  213. Nicolazzo JA, Katneni K. Drug transport across the blood-brain barrier and the impact of breast cancer resistance protein (ABCG2). Curr Top Med Chem. 2009;9(2):130–47.

    CAS  PubMed  Google Scholar 

  214. Ording AG, Garne JP, Nyström PM, Frøslev T, Sørensen HT, Lash TL. Comorbid diseases interact with breast cancer to affect mortality in the first year after diagnosis–a Danish nationwide matched cohort study. PLoS One. 2013;8(10):e76013.

    PubMed Central  CAS  PubMed  Google Scholar 

  215. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992;258(5088):1650–4.

    CAS  PubMed  Google Scholar 

  216. Declèves X, Regina A, Laplanche JL, Roux F, Boval B, Launay JM, et al. Functional expression of P-glycoprotein and multidrug resistance-associated protein (mrp1) in primary cultures of rat astrocytes. J Neurosci Res. 2000;60(5):594–601.

    PubMed  Google Scholar 

  217. Hirrlinger J, König J, Dringen R. Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligodendrocytes, microglial cells and neurones. J Neurochem. 2002;82(3):716–9.

    CAS  PubMed  Google Scholar 

  218. Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood–cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A. 1999;96(7):3900–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  219. Conseil G, Deeley RG, Cole SPC. Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. Pharmacogenet Genomics. 2005;15(8):523–33.

    CAS  PubMed  Google Scholar 

  220. Loe DW, Almquist KC, Deeley RG, Cole SPC. Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles Demonstration of glutathione-dependent vincristine transport. J Biol Chem. 1996;271(16):9675–82.

    CAS  PubMed  Google Scholar 

  221. Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2(1):86–98.

    PubMed Central  PubMed  Google Scholar 

  222. Hofrichter J, Krohn M, Schumacher T, Lange C, Feistel B, Walbroel B, et al. Reduced Alzheimer's disease pathology by St. John's Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice. Curr Alzheimer Res. 2013;10(10):1057–69.

    PubMed Central  CAS  PubMed  Google Scholar 

  223. Sultana R, Butterfield DA. Oxidatively modified GST and MRP1 in Alzheimer's disease brain: implications for accumulation of reactive lipid peroxidation products. Neurochem Res. 2004;29(12):2215–20.

    CAS  PubMed  Google Scholar 

  224. Opazo C, Luza S, Villemagne VL, Volitakis I, Rowe C, Barnham KJ, et al. Radioiodinated clioquinol as a biomarker for β-amyloid: Zn2+ complexes in Alzheimer's disease. Aging Cell. 2006;5(1):69–79.

    CAS  PubMed  Google Scholar 

  225. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron. 2008;59(1):43–55.

    CAS  PubMed  Google Scholar 

  226. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003;30(8):1104–13.

    PubMed  Google Scholar 

  227. Hunt A, Schönknecht P, Henze M, Seidl U, Haberkorn U, Schröder J. Reduced cerebral glucose metabolism in patients at risk for Alzheimer's disease. Psychiatry Res. 2007;155(2):147–54.

    CAS  PubMed  Google Scholar 

  228. Syvänen S, Lindhe Ö, Palner M, Kornum BR, Rahman O, Långström B, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009;37(3):635–43.

    PubMed  Google Scholar 

  229. Han S-H, Mook-Jung I. Diverse molecular targets for therapeutic strategies in Alzheimer's disease. J Korean Med Sci. 2014;29(7):893–902.

    PubMed Central  CAS  PubMed  Google Scholar 

  230. ClinicalTrials.gov. U.S. National Institute of Health.; 2014. http://clinicaltrial.gov/ct2/results?term=new+drug+investigation+in+Alzheimer%27s+disease

  231. Banks WA. Drug delivery to the brain in Alzheimer's disease: Consideration of the blood–brain barrier. Adv Drug Deliv Rev. 2012;64(7):629–39.

    PubMed Central  CAS  PubMed  Google Scholar 

  232. Mehta DC, Short JL, Nicolazzo JA. Memantine transport across the mouse blood-brain barrier is mediated by a cationic influx H + antiporter. Mol Pharm. 2013;10(12):4491–8.

    CAS  PubMed  Google Scholar 

  233. Cornford E, Hyman S. Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy. NeuroRx. 2005;2(1):27–43.

    PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Dharmini C. Mehta & Joseph A. Nicolazzo

  2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Jennifer L. Short

  3. Kolling Institute of Medical Research, Royal North Shore Hospital and Sydney Medical School, The University of Sydney, St Leonards, NSW, Australia

    Sarah N. Hilmer

Authors
  1. Dharmini C. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer L. Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah N. Hilmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph A. Nicolazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph A. Nicolazzo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehta, D.C., Short, J.L., Hilmer, S.N. et al. Drug Access to the Central Nervous System in Alzheimer’s Disease: Preclinical and Clinical Insights. Pharm Res 32, 819–839 (2015). https://doi.org/10.1007/s11095-014-1522-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1522-0

Key Words

Search

Navigation