Skip to main content

Advertisement

SpringerLink
Log in

Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer’s Disease

Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease Guest Editor: Davide Brambilla

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

Abstract

The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer’s disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain.

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

Similar content being viewed by others

Abbreviations

Aβ:

Beta-amyloid

AD:

Alzheimer’s disease

apoE:

Apolipoprotein E

APOER2:

APOE-receptor 2

APP:

Amyloid precursor protein

BBB:

Blood-brain barrier

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

EGF:

Epidermal growth factor

EOAD:

Early-onset Alzheimer’s disease

ISF:

Interstitial fluid

LDLR:

Low-density lipoprotein receptor

LOAD:

Late-onset Alzheimer’s disease

LRP1:

Low-density lipoprotein receptor-related protein-1

LRP2:

Low-density lipoprotein receptor-related protein-2

NMDA:

N-methyl-D-aspartate

PDGF:

Platelet-derived growth factor

PICALM:

Phosphatidylinositol-binding clathrin assembly protein

PS:

Presenilin

RAP:

Receptor-associated protein

sLRP1:

Soluble LRP1

VLDLR:

Very-low density lipoprotein receptor

References

  1. Oeppen J, Vaupel JW. Demography. Broken limits to life expectancy. Science. 2002;296(5570):1029–31.

    CAS  PubMed  Google Scholar 

  2. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75. e2

    PubMed  Google Scholar 

  3. Holtzman DM, Morris JC, Goate AM. Alzheimer's disease: the challenge of the second century. Sci Transl Med. 2011;3(77):77sr1.

    PubMed  PubMed Central  Google Scholar 

  4. Iadecola C. Vascular and Metabolic Factors in Alzheimer's Disease and Related Dementias: Introduction. Cell Mol Neurobiol. 2016;36(2):151–4.

    PubMed  PubMed Central  Google Scholar 

  5. Alzheimer's A. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12(4):459–509.

    Google Scholar 

  6. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76(5):465–79. Epub 1987/11/01

    CAS  PubMed  Google Scholar 

  7. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38. Epub 2011/11/04

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Guerreiro R, Hardy J. Genetics of Alzheimer's disease. Neurotherapeutics. 2014;11(4):732–7.

    PubMed  PubMed Central  Google Scholar 

  9. Karch CM, Cruchaga C, Goate AM. Alzheimer's disease genetics: from the bench to the clinic. Neuron. 2014;83(1):11–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol. 2014;88(4):640–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hardy J. Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimer's Dis: JAD. 2006;9(3 Suppl):151–3. Epub 2006/08/18

    CAS  Google Scholar 

  12. Hardy J. Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res. 2006;3(1):71–3. Epub 2006/02/14

    CAS  PubMed  Google Scholar 

  13. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC. Alzheimer's Disease Neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun. 2016;7:11934. Epub 2016/06/22

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005;28(4):202–8. Epub 2005/04/06

    CAS  PubMed  Google Scholar 

  15. Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993;75(6):1039–42.

    CAS  PubMed  Google Scholar 

  16. Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001;32(2):177–80. Epub 2001/10/31

    CAS  PubMed  Google Scholar 

  17. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284(19):12845–52. Epub 2009/03/14

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pietrzik C, Behl C. Concepts for the treatment of Alzheimer's disease: molecular mechanisms and clinical application. Int J Exp Pathol. 2005;86(3):173–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JA. Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease. Annals N Y Acad Sci. 2002;977:162–8. Epub 2002/12/14

    CAS  Google Scholar 

  20. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004;5(5):347–60. Epub 2004/04/22

    CAS  PubMed  Google Scholar 

  21. Iadecola C. Vascular and Metabolic Factors in Alzheimer's Disease and Related Dementias: Introduction. Cell Mol Neurobiol. 2016;36:151–4.

    PubMed  PubMed Central  Google Scholar 

  22. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 2009;118(1):103–13. Epub 2009/03/26

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201. Epub 2008/01/25

    CAS  PubMed  Google Scholar 

  24. Meister S, Storck SE, Hameister E, Behl C, Weggen S, Clement AM, et al. Expression of the ALS-causing variant hSOD1(G93A) leads to an impaired integrity and altered regulation of claudin-5 expression in an in vitro blood-spinal cord barrier model. J Cereb Blood Flow Metab. 2015;35(7):1112–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36(10):587–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8(1):7.

    PubMed  PubMed Central  Google Scholar 

  27. Bovetti S, Hsieh YC, Bovolin P, Perroteau I, Kazunori T, Puche AC. Blood vessels form a scaffold for neuroblast migration in the adult olfactory bulb. J Neurosci. 2007;27(22):5976–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pardridge WM. Molecular biology of the blood-brain barrier. Methods Mol Med. 2003;89:385–99.

    CAS  PubMed  Google Scholar 

  29. Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T. Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease. Proc Nat Acad Sci U S A. 2008;105(9):3587–92.

    CAS  Google Scholar 

  30. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412.

    PubMed  PubMed Central  Google Scholar 

  31. van de Haar HJ, Burgmans S, Jansen JF, van Osch MJ, van Buchem MA, Muller M, et al. Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. Radiology. 2016;281(2):527–35. Epub 2016/10/19

    PubMed  Google Scholar 

  32. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302. Epub 2015/01/23

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wyss-Coray T, McConlogue L, Kindy M, Schmidt AM, Du Yan S, Stern DM. Key signaling pathways regulate the biological activities and accumulation of amyloid-beta. Neurobiol Aging. 2001;22(6):967–73. Epub 2002/01/05

    CAS  PubMed  Google Scholar 

  34. Naslund J, Schierhorn A, Hellman U, Lannfelt L, Roses AD, Tjernberg LO, et al. Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Nat Acad Sci U S A. 1994;91(18):8378–82.

    CAS  Google Scholar 

  35. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999;46(6):860–6. Epub 1999/12/10

    CAS  PubMed  Google Scholar 

  36. Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, et al. The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain: J Neurol. 2010;133(Pt 5):1328–41. Epub 2010/04/21

    Google Scholar 

  37. Lei M, Xu H, Li Z, Wang Z, O'Malley TT, Zhang D, et al. Soluble Abeta oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol Dis. 2016;85:111–21.

    CAS  PubMed  Google Scholar 

  38. Ferreira ST, Lourenco MV, Oliveira MM, De Felice FG. Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease. Front Cell Neurosci. 2015;9:191.

    PubMed  PubMed Central  Google Scholar 

  39. Bao F, Wicklund L, Lacor PN, Klein WL, Nordberg A, Marutle A. Different beta-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity. Neurobiol Aging. 2012;33(4):825 e1–13. Epub 2011/06/21

    Google Scholar 

  40. Bjorklund NL, Reese LC, Sadagoparamanujam VM, Ghirardi V, Woltjer RL, Taglialatela G. Absence of amyloid beta oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer's disease neuropathology. Mol Neurodegener. 2012;7:23. Epub 2012/05/30

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao J, O'Connor T, Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer's disease pathogenesis. J Neuroinflammation. 2011;8:150.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Berkenbosch F, Refolo LM, Friedrich VL Jr, Casper D, Blum M, Robakis NK. The Alzheimer's amyloid precursor protein is produced by type I astrocytes in primary cultures of rat neuroglia. J Neurosci Res. 1990;25(3):431–40.

    CAS  PubMed  Google Scholar 

  43. Frackowiak J, Potempska A, LeVine H, Haske T, Dickson D, Mazur-Kolecka B. Extracellular deposits of A beta produced in cultures of Alzheimer disease brain vascular smooth muscle cells. J Neuropathol Exp Neurol. 2005;64(1):82–90. Epub 2005/02/18

    CAS  PubMed  Google Scholar 

  44. Kitazume S, Tachida Y, Kato M, Yamaguchi Y, Honda T, Hashimoto Y, et al. Brain endothelial cells produce amyloid {beta} from amyloid precursor protein 770 and preferentially secrete the O-glycosylated form. J Biol Chem. 2010;285(51):40097–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Devraj K, Poznanovic S, Spahn C, Schwall G, Harter PN, Mittelbronn M, et al. BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease. J Cereb Blood Flow Metab. 2016;36(7):1281–94.

    CAS  PubMed  Google Scholar 

  46. Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Munzer P, et al. Blood platelets in the progression of Alzheimer's disease. PLoS One. 2014;9(2):e90523. Epub 2014/03/04

    PubMed  PubMed Central  Google Scholar 

  47. Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Nat Acad Sci U S A. 1994;91(25):11993–7. Epub 1994/12/06

    CAS  Google Scholar 

  48. Jiang S, Zhang M, Ren D, Tang G, Lin S, Qian Y, et al. Enhanced production of amyloid precursor protein mRNA by peripheral mononuclear blood cell in Alzheimer's disease. Am J Med Genet Part B, Neuropsychiatr Genet. 2003;118B(1):99–102. Epub 2003/03/11

    Google Scholar 

  49. Pohlkamp T, Wasser CR, Herz J. Functional Roles of the Interaction of APP and Lipoprotein Receptors. Front Mol Neurosci. 2017;10:54. Epub 2017/03/17

    PubMed  PubMed Central  Google Scholar 

  50. Lleo A, Waldron E, von Arnim CA, Herl L, Tangredi MM, Peltan ID, et al. Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase. J Biol Chem. 2005;280(29):27303–9. Epub 2005/05/27

    CAS  PubMed  Google Scholar 

  51. Yoon IS, Pietrzik CU, Kang DE, Koo EH. Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid beta protein production via the beta-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling. J Biol Chem. 2005;280(20):20140–7. Epub 2005/03/18

    CAS  PubMed  Google Scholar 

  52. Pietrzik CU, Busse T, Merriam DE, Weggen S, Koo EH. The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing. EMBO J. 2002;21(21):5691–700. Epub 2002/11/02

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A, et al. Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J Biol Chem. 1992;267(1):546–54.

    CAS  PubMed  Google Scholar 

  54. Kuo YM, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, et al. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem. 1996;271(8):4077–81.

    CAS  PubMed  Google Scholar 

  55. 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 

  56. Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003;62(9):885–98. Epub 2003/10/10

    CAS  PubMed  Google Scholar 

  57. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, et al. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004;279(19):20296–306. Epub 2004/02/27

    CAS  PubMed  Google Scholar 

  58. Schonherr C, Bien J, Isbert S, Wichert R, Prox J, Altmeppen H, et al. Generation of aggregation prone N-terminally truncated amyloid beta peptides by meprin beta depends on the sequence specificity at the cleavage site. Mol Neurodegener. 2016;11:19. Epub 2016/02/21

    PubMed  PubMed Central  Google Scholar 

  59. Wirths O, Erck C, Martens H, Harmeier A, Geumann C, Jawhar S, et al. Identification of low molecular weight pyroglutamate A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem. 2010;285(53):41517–24. Epub 2010/10/26

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kumar S, Walter J. Phosphorylation of amyloid beta (Abeta) peptides - a trigger for formation of toxic aggregates in Alzheimer's disease. Aging. 2011;3(8):803–12. Epub 2011/08/27

    PubMed  PubMed Central  Google Scholar 

  61. Saito S, Ihara M. New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy. FrontAging Neurosci. 2014;6:290.

    Google Scholar 

  62. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330(6012):1774. Epub 2010/12/15

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006;12(7):856–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Miners JS, Van Helmond Z, Chalmers K, Wilcock G, Love S, Kehoe PG. Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2006;65(10):1012–21.

    CAS  PubMed  Google Scholar 

  65. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40(6):1087–93.

    CAS  PubMed  Google Scholar 

  66. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106(12):1489–99. Epub 2000/12/20

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015;11(8):457–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27(5):909–18. Epub 2006/11/02

    CAS  PubMed  Google Scholar 

  69. Storck SE, Meister S, Nahrath J, Meissner JN, Schubert N, Di Spiezio A, et al. Endothelial LRP1 transports amyloid-beta1-42 across the blood-brain barrier. J Clin Invest. 2016;126(1):123–36.

    PubMed  Google Scholar 

  70. Ito S, Ohtsuki S, Kamiie J, Nezu Y, Terasaki T. Cerebral clearance of human amyloid-beta peptide (1-40) across the blood-brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes. J Neurochem. 2007;103(6):2482–90. Epub 2007/10/03

    CAS  PubMed  Google Scholar 

  71. Ito S, Ueno T, Ohtsuki S, Terasaki T. Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-beta peptide(1-40) in mouse: involvement of an LRP-1-independent pathway. J Neurochem. 2010;113(5):1356–63. Epub 2010/04/07

    CAS  PubMed  Google Scholar 

  72. Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008;88(3):887–918. Epub 2008/07/16

    CAS  PubMed  Google Scholar 

  73. Nazer B, Hong S, Selkoe DJ. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiol Dis. 2008;30(1):94–102. Epub 2008/02/22

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-beta. J Neurosci. 2012;32(46):16458–65. Epub 2012/11/16

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, et al. Neuronal clearance of amyloid-beta by endocytic receptor LRP1. J Neurosci. 2013;33(49):19276–83. Epub 2013/12/07

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol. 1998;153(3):725–33. Epub 1998/09/15

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Weller RO. Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exper Neurol. 1998;57(10):885–94. Epub 1998/10/24

    CAS  Google Scholar 

  78. Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, et al. Astrocytic LRP1 Mediates Brain Abeta Clearance and Impacts Amyloid Deposition. J Neurosci. 2017;37(15):4023–31. Epub 2017/03/10

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Fujiyoshi M, Tachikawa M, Ohtsuki S, Ito S, Uchida Y, Akanuma S, et al. Amyloid-beta peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. J Neurochem. 2011;118(3):407–15.

    CAS  PubMed  Google Scholar 

  80. Pascale CL, Miller MC, Chiu C, Boylan M, Caralopoulos IN, Gonzalez L, et al. Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent. Fluids Barriers CNS. 2011;8:21. Epub 2011/07/12

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Strazielle N, Ghersi-Egea JF. Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier. Curr Pharm Des. 2016;22(35):5463–76. Epub 2016/07/29

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Zheng G, Bachinsky DR, Stamenkovic I, Strickland DK, Brown D, Andres G, et al. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). J Histochem Cytochem. 1994;42(4):531–42. Epub 1994/04/01

    CAS  PubMed  Google Scholar 

  83. Crossgrove JS, Li GJ, Zheng W. The choroid plexus removes beta-amyloid from brain cerebrospinal fluid. Exp Biol Med. 2005;230(10):771–6. Epub 2005/10/26

    CAS  Google Scholar 

  84. Crouthamel MH, Kelly EJ, Ho RJ. Development and characterization of transgenic mouse models for conditional gene knockout in the blood-brain and blood-CSF barriers. Transgenic Res. 2012;21(1):113–30. Epub 2011/05/04

    CAS  PubMed  Google Scholar 

  85. Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Nat Acad Sci U S A. 1989;86(15):5810–4. Epub 1989/08/01

    CAS  Google Scholar 

  86. Williams SE, Ashcom JD, Argraves WS, Strickland DK. A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. J Biol Chem. 1992;267(13):9035–40. Epub 1992/05/05

    CAS  PubMed  Google Scholar 

  87. Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991;266(31):21232–8. Epub 1991/11/05

    CAS  PubMed  Google Scholar 

  88. Willnow TE, Armstrong SA, Hammer RE, Herz J. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Nat Acad Sc U S A. 1995;92(10):4537–41. Epub 1995/05/09

    CAS  Google Scholar 

  89. Kanekiyo T, Zhang J, Liu Q, Liu CC, Zhang L, Bu G. Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci. 2011;31(5):1644–51. Epub 2011/02/04

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015;18(7):978–87. Epub 2015/05/26

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Candela P, Saint-Pol J, Kuntz M, Boucau MC, Lamartiniere Y, Gosselet F, et al. In vitro discrimination of the role of LRP1 at the BBB cellular level: Focus on brain capillary endothelial cells and brain pericytes. Brain Res. 2015;1594:15–26. Epub 2014/12/03

    CAS  PubMed  Google Scholar 

  92. Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid beta-peptide elimination from the brain. J Neurochem. 2010;115(5):1077–89. Epub 2010/09/22

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Neels JG, van Den Berg BM, Lookene A, Olivecrona G, Pannekoek H, van Zonneveld AJ. The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties. J Biol Chem. 1999;274(44):31305–11. Epub 1999/10/26

    CAS  PubMed  Google Scholar 

  94. Westein E, Denis CV, Bouma BN, Lenting PJ. The alpha -chains of C4b-binding protein mediate complex formation with low density lipoprotein receptor-related protein. J Biol Chem. 2002;277(4):2511–6. Epub 2001/11/14

    CAS  PubMed  Google Scholar 

  95. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43(3):333–44. Epub 2004/08/06

    CAS  PubMed  Google Scholar 

  96. Herz J, Clouthier DE, Hammer RE. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1992;71(3):411–21. Epub 1992/10/30

    CAS  PubMed  Google Scholar 

  97. Rabiej VK, Pflanzner T, Wagner T, Goetze K, Storck SE, Eble JA, et al. Low density lipoprotein receptor-related protein 1 mediated endocytosis of beta1-integrin influences cell adhesion and cell migration. Exp Cell Res. 2016;340(1):102–15.

    CAS  PubMed  Google Scholar 

  98. Mikhailenko I, Battey FD, Migliorini M, Ruiz JF, Argraves K, Moayeri M, et al. Recognition of alpha 2-macroglobulin by the low density lipoprotein receptor-related protein requires the cooperation of two ligand binding cluster regions. J Biol Chem. 2001;276(42):39484–91. Epub 2001/08/17

    CAS  PubMed  Google Scholar 

  99. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001;108(6):779–84. Epub 2001/09/19

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Roebroek AJ, Reekmans S, Lauwers A, Feyaerts N, Smeijers L, Hartmann D. Mutant Lrp1 knock-in mice generated by recombinase-mediated cassette exchange reveal differential importance of the NPXY motifs in the intracellular domain of LRP1 for normal fetal development. Mol Cell Biol. 2006;26(2):605–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Reekmans SM, Pflanzner T, Gordts PL, Isbert S, Zimmermann P, Annaert W, et al. Inactivation of the proximal NPXY motif impairs early steps in LRP1 biosynthesis. Cell Mol Life Sci: CMLS. 2010;67(1):135–45.

    CAS  PubMed  Google Scholar 

  102. Li Y, Lu W, Marzolo MP, Bu G. Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. J Biol Chem. 2001;276(21):18000–6. Epub 2001/03/30

    CAS  PubMed  Google Scholar 

  103. van Kerkhof P. Alves dos Santos CM, Sachse M, Klumperman J, Bu G, Strous GJ. Proteasome inhibitors block a late step in lysosomal transport of selected membrane but not soluble proteins. Mol Biol Cell. 2001;12(8):2556–66. Epub 2001/08/22

    PubMed  PubMed Central  Google Scholar 

  104. Pflanzner T, Janko MC, Andre-Dohmen B, Reuss S, Weggen S, Roebroek AJ, et al. LRP1 mediates bidirectional transcytosis of amyloid-beta across the blood-brain barrier. Neurobiol Aging. 2011;32(12):2323 e1-11. Epub 2010/07/16.

  105. Gonias SL, Wu L, Salicioni AM. Low density lipoprotein receptor-related protein: regulation of the plasma membrane proteome. Thromb Haemost. 2004;91(6):1056–64. Epub 2004/06/04

    CAS  PubMed  Google Scholar 

  106. Herr UM, Strecker P, Storck SE, Thomas C, Rabiej V, Junker A, et al. LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State. Front Mol Neurosci. 2017;10:118. Epub 2017/05/13

    PubMed  PubMed Central  Google Scholar 

  107. Maier W, Bednorz M, Meister S, Roebroek A, Weggen S, Schmitt U, et al. LRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype. Mol Neurodegener. 2013;8:25. Epub 2013/07/23

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Muratoglu SC, Mikhailenko I, Newton C, Migliorini M, Strickland DK. Low density lipoprotein receptor-related protein 1 (LRP1) forms a signaling complex with platelet-derived growth factor receptor-beta in endosomes and regulates activation of the MAPK pathway. J Biol Chem. 2010;285(19):14308–17. Epub 2010/03/12

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Weaver AM, Hussaini IM, Mazar A, Henkin J, Gonias SL. Embryonic fibroblasts that are genetically deficient in low density lipoprotein receptor-related protein demonstrate increased activity of the urokinase receptor system and accelerated migration on vitronectin. J Biol Chem. 1997;272(22):14372–9. Epub 1997/05/30

    CAS  PubMed  Google Scholar 

  110. Shackleton B, Crawford F, Bachmeier C. Inhibition of ADAM10 promotes the clearance of Abeta across the BBB by reducing LRP1 ectodomain shedding. Fluids Barriers CNS. 2016;13(1):14.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, et al. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem. 2005;280(18):17777–85.

    Google Scholar 

  112. Derocq D, Prebois C, Beaujouin M, Laurent-Matha V, Pattingre S, Smith GK, et al. Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis. Oncogene. 2012;31(26):3202–12. Epub 2011/11/15

    CAS  PubMed  Google Scholar 

  113. Zurhove K, Nakajima C, Herz J, Bock HH, May P. Gamma-secretase limits the inflammatory response through the processing of LRP1. Sci Signal. 2008;1(47):ra15. Epub 2008/11/28.

  114. Bachmeier C, Shackleton B, Ojo J, Paris D, Mullan M, Crawford F. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. Neuromolecular Med. 2014;16(4):686–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Quinn KA, Grimsley PG, Dai YP, Tapner M, Chesterman CN, Owensby DA. Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. J Biol Chem. 1997;272(38):23946–51.

    CAS  PubMed  Google Scholar 

  116. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, et al. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med. 2007;13(9):1029–31. Epub 2007/08/19

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cam JA, Zerbinatti CV, Li Y, Bu G. Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein. J Biol Chem. 2005;280(15):15464–70.

    CAS  PubMed  Google Scholar 

  118. Zerbinatti CV, Wozniak DF, Cirrito J, Cam JA, Osaka H, Bales KR, et al. Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Pro Nat Acad Sci U S A. 2004;101(4):1075–80. Epub 2004/01/21

    CAS  Google Scholar 

  119. Osgood D, Miller MC, Messier AA, Gonzalez L, Silverberg GD. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. Neurobiol Aging. 2017;57:178–85. Epub 2017/06/28

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, et al. Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest. 2000;106(9):1159–66. Epub 2000/11/09

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 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. Epub 2009/12/17

    CAS  PubMed  Google Scholar 

  122. Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, et al. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2009;11(2):143–53. Epub 2008/12/23

    CAS  PubMed  Google Scholar 

  123. Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, et al. Cerebral blood flow in Alzheimer's disease. Vasc Health Risk Manag. 2012;8:599–611. Epub 2012/10/31

    PubMed  PubMed Central  Google Scholar 

  124. Arelin K, Kinoshita A, Whelan CM, Irizarry MC, Rebeck GW, Strickland DK, et al. LRP and senile plaques in Alzheimer's disease: colocalization with apolipoprotein E and with activated astrocytes. Brain Res Mol Brain Res. 2002;104(1):38–46.

    CAS  PubMed  Google Scholar 

  125. Erickson MA, Niehoff ML, Farr SA, Morley JE, Dillman LA, Lynch KM, et al. Peripheral administration of antisense oligonucleotides targeting the amyloid-beta protein precursor reverses AbetaPP and LRP-1 overexpression in the aged SAMP8 mouse brain. J Alzheimer's Dis: JAD. 2012;28(4):951–60.

    CAS  Google Scholar 

  126. Bouter Y, Kacprowski T, Weissmann R, Dietrich K, Borgers H, Brauss A, et al. Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer's disease by deep sequencing. Front Aging Neurosci. 2014;6:75. Epub 2014/05/06

    PubMed  PubMed Central  Google Scholar 

  127. 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  PubMed Central  Google Scholar 

  128. Yan FL, Zheng Y, Zhao FD. Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia. Acta Neuropathol. 2008;116(5):529–35. Epub 2008/10/03

    PubMed  Google Scholar 

  129. Rebeck GW, Harr SD, Strickland DK, Hyman BT. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Ann Neurol. 1995;37(2):211–7. Epub 1995/02/01

    CAS  PubMed  Google Scholar 

  130. Navarro A, Del Valle E, Astudillo A. Gonzalez del Rey C, Tolivia J. Immunohistochemical study of distribution of apolipoproteins E and D in human cerebral beta amyloid deposits. Exp Neurol. 2003;184(2):697–704. Epub 2004/02/11

    CAS  PubMed  Google Scholar 

  131. Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, et al. Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A. 2012;109(9):3510–5. Epub 2012/02/07

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sagare AP, Bell RD, Srivastava A, Sengillo JD, Singh I, Nishida Y, et al. A lipoprotein receptor cluster IV mutant preferentially binds amyloid-beta and regulates its clearance from the mouse brain. J Biol Chem. 2013;288(21):15154–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Walker JR, Pacoma R, Watson J, Ou W, Alves J, Mason DE, et al. Enhanced proteolytic clearance of plasma Abeta by peripherally administered neprilysin does not result in reduced levels of brain Abeta in mice. J Neurosci. 2013;33(6):2457–64. Epub 2013/02/09

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Henderson SJ, Andersson C, Narwal R, Janson J, Goldschmidt TJ, Appelkvist P, et al. Sustained peripheral depletion of amyloid-beta with a novel form of neprilysin does not affect central levels of amyloid-beta. Brain. 2014;137(Pt 2):553–64. Epub 2013/11/22

    PubMed  Google Scholar 

  135. Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014;17(5):661–3. Epub 2014/04/15

    CAS  PubMed  Google Scholar 

  136. Abbott A, Dolgin E. Failed Alzheimer's trial does not kill leading theory of disease. Nature. 2016;540(7631):15–6. Epub 2016/12/03

    CAS  PubMed  Google Scholar 

  137. Pahnke J, Walker LC, Scheffler K, Krohn M. Alzheimer's disease and blood-brain barrier function-Why have anti-beta-amyloid therapies failed to prevent dementia progression? Neurosci Biobehav Rev. 2009;33(7):1099–108. Epub 2009/06/02

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Toyn J. What lessons can be learned from failed Alzheimer's disease trials? Expert review of clinical pharmacology. 2015;8(3):267–9. Epub 2015/04/11

    CAS  PubMed  Google Scholar 

  139. Kuang E, Wan Q, Li X, Xu H, Zou T, Qi Y. ER stress triggers apoptosis induced by Nogo-B/ASY overexpression. Exp Cell Res. 2006;312(11):1983–8. Epub 2006/05/12

    CAS  PubMed  Google Scholar 

  140. Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002–13. Epub 2008/11/27

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lang MF, Salinin S, Ridder DA, Kleesiek J, Hroudova J, Berger S, et al. A transgenic approach to identify thyroxine transporter-expressing structures in brain development. J Neuroendocrinol. 2011;23(12):1194–203.

    CAS  PubMed  Google Scholar 

  142. Zheng PP, Romme E, van der Spek PJ, Dirven CM, Willemsen R, Kros JM. Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol. 2010;68(6):835–44. Epub 2011/01/05

    CAS  PubMed  Google Scholar 

  143. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509(7501):507–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Shinohara M, Sato N, Kurinami H, Takeuchi D, Takeda S, Shimamura M, et al. Reduction of brain beta-amyloid (Abeta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Abeta clearance. J Biol Chem. 2010;285(29):22091–102. Epub 2010/05/18

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956–64. Epub 2010/03/05

    CAS  PubMed  Google Scholar 

  146. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77(6):556–63. Epub 2011/07/29

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Geifman N, Brinton RD, Kennedy RE, Schneider LS, Butte AJ. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimer’s Res Ther. 2017;9(1):10. Epub 2017/02/19

  148. Santos LM, Rodrigues D, Alemi M, Silva SC, Ribeiro CA, Cardoso I. Resveratrol administration increases Transthyretin protein levels ameliorating AD features - importance of transthyretin tetrameric stability. Mol Med. 2016;22:597–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Batarseh YS, Bharate SS, Kumar V, Kumar A, Vishwakarma RA, Bharate SB, et al. Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid beta Load and Related Toxicity in 5XFAD Mice. ACS Chem Nerosci. 2017;8(8):1756–66.

    CAS  PubMed  Google Scholar 

  150. Qosa H, Batarseh YS, Mohyeldin MM, El Sayed KA, Keller JN, Kaddoumi A. Oleocanthal enhances amyloid-beta clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model. ACS Chem Nerosci. 2015;6(11):1849–59. Epub 2015/09/09

    CAS  Google Scholar 

  151. Qosa H, Abuznait AH, Hill RA, Kaddoumi A. Enhanced brain amyloid-beta clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer's disease. Journal of Alzheimer's disease: JAD. 2012;31(1):151–65.

    CAS  PubMed  Google Scholar 

  152. Mao H, Xie L, Pi X. Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis. Front Cardiovasc Med. 2017;4:34.

    PubMed  PubMed Central  Google Scholar 

  153. Pi X, Schmitt CE, Xie L, Portbury AL, Wu Y, Lockyer P, et al. LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis. Circ Res. 2012;111(5):564–74. Epub 2012/07/11

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Nakajima C, Haffner P, Goerke SM, Zurhove K, Adelmann G, Frotscher M, et al. The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development. Development. 2014;141(23):4513–25. Epub 2014/11/08

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 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 

  156. Kreuter J. Drug delivery to the central nervous system by polymeric nanoparticles: what do we know? Adv Drug Deliv Rev. 2014;71:2–14.

    CAS  PubMed  Google Scholar 

  157. Pardridge WM. Drug and gene delivery to the brain: the vascular route. Neuron. 2002;36(4):555–8.

    CAS  PubMed  Google Scholar 

  158. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.

    PubMed  PubMed Central  Google Scholar 

  159. Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016;13(7):963–75.

    CAS  PubMed  Google Scholar 

  160. Mehta DC, Short JL, Hilmer SN, Nicolazzo JA. Drug access to the central nervous system in Alzheimer's disease: preclinical and clinical insights. Pharm Res. 2015;32(3):819–39. Epub 2014/10/17

    CAS  PubMed  Google Scholar 

  161. Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40(3):648–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Coomber BL, Stewart PA. Morphometric analysis of CNS microvascular endothelium. Microvasc Res. 1985;30(1):99–115.

    CAS  PubMed  Google Scholar 

  163. Demeule M, Currie JC, Bertrand Y, Che C, Nguyen T, Regina A, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008;106(4):1534–44.

    CAS  PubMed  Google Scholar 

  164. Meister S, Zlatev I, Stab J, Docter D, Baches S, Stauber RH, et al. Nanoparticulate flurbiprofen reduces amyloid-beta42 generation in an in vitro blood-brain barrier model. Alzheimer's Res Ther. 2013;5(6):51. Epub 2013/11/28

    Google Scholar 

  165. Patel T, Zhou J, Piepmeier JM, Saltzman WM. Polymeric nanoparticles for drug delivery to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):701–5.

    CAS  PubMed  Google Scholar 

  166. Silva GA. Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system. Ann N Y Acad Sci. 2010;1199:221–30.

    CAS  PubMed  Google Scholar 

  167. Tian X, Nyberg S, SS P, Madsen J, Daneshpour N, Armes SP, et al. LRP-1-mediated intracellular antibody delivery to the Central Nervous System. Sci Rep. 2015;5:11990.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Tosi G, Costantino L, Ruozi B, Forni F, Vandelli MA. Polymeric nanoparticles for the drug delivery to the central nervous system. Expert Opin Drug Deliv. 2008;5(2):155–74.

    CAS  PubMed  Google Scholar 

  169. Niewoehner J, Bohrmann B, Collin L, Urich E, Sade H, Maier P, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81(1):49–60.

    CAS  PubMed  Google Scholar 

  170. Yu YJ, Atwal JK, Zhang Y, Tong RK, Wildsmith KR, Tan C, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med. 2014;6(261):261ra154.

    PubMed  Google Scholar 

  171. Zuchero YJ, Chen X, Bien-Ly N, Bumbaca D, Tong RK, Gao X, et al. Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies. Neuron. 2016;89(1):70–82.

    CAS  PubMed  Google Scholar 

  172. Che C, Yang G, Thiot C, Lacoste MC, Currie JC, Demeule M, et al. New Angiopep-modified doxorubicin (ANG1007) and etoposide (ANG1009) chemotherapeutics with increased brain penetration. J Med Chem. 2010;53(7):2814–24.

    CAS  PubMed  Google Scholar 

  173. Regina A, Demeule M, Che C, Lavallee I, Poirier J, Gabathuler R, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol. 2008;155(2):185–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Han S, Zheng H, Lu Y, Sun Y, Huang A, Fei W, et al. A Novel Synergetic Targeting Strategy for Glioma Therapy Employing Borneol Combination with Angiopep-2-modified. DOX-loaded PAMAM Dendrimer. J Drug Target. 2017:1–20.

  175. Lu F, Pang Z, Zhao J, Jin K, Li H, Pang Q, et al. Angiopep-2-conjugated poly(ethylene glycol)-co- poly(epsilon-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats. Int J Nanomedicine. 2017;12:2117–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Kafa H, Wang JT, Rubio N, Klippstein R, Costa PM, Hassan HA, et al. Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood-brain barrier in vitro and in vivo. J Control Release. 2016;225:217–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Thomas FC, Taskar K, Rudraraju V, Goda S, Thorsheim HR, Gaasch JA, et al. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res. 2009;26(11):2486–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Kim JA, Casalini T, Brambilla D, Leroux JC. Presumed LRP1-targeting transport peptide delivers beta-secretase inhibitor to neurons in vitro with limited efficiency. Sci Rep-Uk. 2016;6:34297.

    CAS  Google Scholar 

  180. Grossen P, Witzigmann D, Sieber S, Huwyler J. PEG-PCL-based nanomedicines: A biodegradable drug delivery system and its application. J Control Release. 2017;260:46–60. Epub 2017/05/26

    CAS  PubMed  Google Scholar 

  181. Zensi A, Begley D, Pontikis C, Legros C, Mihoreanu L, Wagner S, et al. Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones. J Control Release. 2009;137(1):78–86. Epub 2009/03/17

    CAS  PubMed  Google Scholar 

  182. Linton MF, Gish R, Hubl ST, Butler E, Esquivel C, Bry WI, et al. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Invest. 1991;88(1):270–81. Epub 1991/07/01

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments and Disclosures

We thank Michael Plenikowski and Dr. Sabrina Meister for contributing to the illustrations and Julius Nahrath for the assistance in the immunohistochemical analysis of mouse brains. This article was funded in part by DFG (PI 379/8-1), Bundesministerium für Bildung und Forschung (01ED1605) to C.U.P., S.S. was supported by the intramural funding program of the University Medical Center of the Johannes-Gutenberg University Mainz. The authors have declared that no conflict of interest exists.

Author information

Authors and Affiliations

  1. Molecular Neurodegeneration, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099, Mainz, Germany

    Steffen E. Storck & Claus U. Pietrzik

Authors
  1. Steffen E. Storck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claus U. Pietrzik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claus U. Pietrzik.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Storck, S.E., Pietrzik, C.U. Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer’s Disease. Pharm Res 34, 2637–2651 (2017). https://doi.org/10.1007/s11095-017-2267-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-017-2267-3

KEY WORDS

Search

Navigation