Pharmaceutical Research

, Volume 23, Issue 7, pp 1407–1416

Major Involvement of Low-Density Lipoprotein Receptor-Related Protein 1 in the Clearance of Plasma Free Amyloid β-Peptide by the Liver

  • Chihiro Tamaki
  • Sumio Ohtsuki
  • Takeshi Iwatsubo
  • Tadafumi Hashimoto
  • Kaoru Yamada
  • Chiori Yabuki
  • Tetsuya Terasaki
Featured Article


To identify the molecules responsible for amyloid β-peptide (1–40) (Aβ(1–40)) uptake by the liver, which play a major role in the systemic clearance of Aβ(1–40).


The liver uptake index method was used to examine the mechanisms of Aβ(1–40) uptake by the liver in vivo.


[125I]Aβ(1–40) uptake by the rat liver was concentration-dependent (50% saturation concentration = 302 nM). The inhibitory spectrum of Aβ fragments indicated that 17–24 in Aβ (LVFFAEDV) was the putative sequence responsible for hepatic Aβ(1–40) uptake. Receptor-associated protein (RAP) inhibited [125I]Aβ(1–40) uptake by 48%. RAP-deficient mice, in which low-density lipoprotein receptor-related protein 1 (LRP-1) expression was suppressed, showed a 46% reduction in [125I]Aβ(1–40) uptake by the liver. siRNA-mediated suppression of LRP-1 expression in the liver resulted in a reduction in [125I]Aβ(1–40) uptake by 64%. Both the expression of LRP-1 in the liver and the hepatic Aβ(1–40) uptake were significantly reduced in 13-month-old rats compared with 7-week-old rats.


LRP-1 is the major receptor responsible for the saturable uptake of plasma free Aβ(1–40) by the liver. Reduction of LRP-1 expression will play a role in the age-related reduction in hepatic Aβ(1–40) clearance.

Key Words

amyloid β-peptide clearance liver uptake index low-density lipoprotein receptor-related protein 1 receptor-mediated endocytosis 


amyloid β-peptide


Alzheimer's disease


advanced glycation end products


apolipoprotein E


blood–brain barrier


bovine serum albumin


cerebrovascular amyloid angiopathy




low-density lipoprotein


LDL receptor-related protein 1


liver uptake index


receptor for AGEs


receptor-associated protein


sodium dodecylsulfate


short interfering RNA


scavenger receptor type A


  1. 1.
    Castano, E. M., Prelli, F., Soto, C., Beavis, R., Matsubara, E., Shoji, M., Frangione, B. 1996The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1–42 in Alzheimer's diseaseJ. Biol. Chem.2713218532191PubMedCrossRefGoogle Scholar
  2. 2.
    Citron, M., Diehl, T. S., Gordon, G., Biere, A. L., Seubert, P., Selkoe, D. J. 1996Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activitiesProc. Natl. Acad. Sci. USA931317013175PubMedCrossRefGoogle Scholar
  3. 3.
    Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schlossmacher, M., Whaley, J., Swindlehurst, C., Mccormack, R., Wolfert, R., Selkou, D. J., Lieberburg, I., Schenk, D. 1992Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluidsNature359325327PubMedCrossRefGoogle Scholar
  4. 4.
    Biere, A. L., Ostaszewski, B., Stimson, E. R., Hyman, B. T., Maggio, J. E., Selkoe, D. J. 1996Amyloid beta-peptide is transported on lipoproteins and albumin in human plasmaJ. Biol. Chem.2713291632922PubMedCrossRefGoogle Scholar
  5. 5.
    Poduslo, J. F., Curran, G. L., Haggard, J. J., Biere, A. L., Selkoe, D. J. 1997Permeability and residual plasma volume of human, Dutch variant, and rat amyloid beta-protein 1-40 at the blood–brain barrierNeurobiol. Dis.42734PubMedCrossRefGoogle Scholar
  6. 6.
    Hone, E., Martins, I. J., Fonte, J., Martins, R. N. 2003Apolipoprotein E influences amyloid-beta clearance from the murine peripheryJ. Alzheimer's Dis.518Google Scholar
  7. 7.
    Ghiso, J., Shayo, M., Calero, M., Ng, D., Tomidokoro, Y., Gandy, S., Rostagno, A., Frangione, B. 2004Systemic catabolism of Alzheimer's Abeta 40 and Abeta 42J. Biol. Chem.2794589745908PubMedCrossRefGoogle Scholar
  8. 8.
    Kandimalla, K. K., Curran, G. L., Holasek, S. S., Gilles, E. J., Wengenack, T. M., Poduslo, J. F. 2005Pharmacokinetic analysis of the blood–brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP, PS1) and its implications for amyloid plaque formationJ. Pharmacol. Exp. Ther.31313701378PubMedCrossRefGoogle Scholar
  9. 9.
    Mackic, J. B., Weiss, M. H., Miao, W., Kirkman, E., Ghiso, J., Calero, M., Bading, J., Frangione, B., Zlokovic, B. V. 1998Cerebrovascular accumulation and increased blood–brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathyJ. Neurochem.70210215PubMedCrossRefGoogle Scholar
  10. 10.
    Mackic, J. B., Bading, J., Ghiso, J., Walker, L., Wisniewski, T., Frangione, B., Zlokovic, B. V. 2002Circulating amyloid-beta peptide crosses the blood–brain barrier in aged monkeys and contributes to Alzheimer's disease lesionsVascul. Pharmacol.38303313PubMedCrossRefGoogle Scholar
  11. 11.
    Smith, C. C., Betteridge, D. J. 2004Plasma beta-amyloid (A beta) 40 concentration, lipid status and age in humansNeurosci. Lett.3674850PubMedCrossRefGoogle Scholar
  12. 12.
    Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., Roses, A. D. 1993Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer diseaseProc. Natl. Acad. Sci. USA9080988102PubMedCrossRefGoogle Scholar
  13. 13.
    Herz, J., Strickland, D. K. 2001LRP: a multifunctional scavenger and signaling receptorJ. Clin. Invest.108779784PubMedCrossRefGoogle Scholar
  14. 14.
    Shibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J., Zlokovic, B. V. 2000Clearance of Alzheimer's amyloid-beta(1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrierJ. Clin. Invest.10614891499PubMedGoogle Scholar
  15. 15.
    Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H. W., Spijkers, P., Guo, H., Song, X., Lenting, P. J., Nostrand, W. E., Zlokovic, B. V. 2004LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoformsNeuron43333344PubMedCrossRefGoogle Scholar
  16. 16.
    Moestrup, S. K., Gliemann, J., Pallesen, G. 1992Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissuesCell Tissue Res.269375382PubMedCrossRefGoogle Scholar
  17. 17.
    Pardridge, W. M., Mietus, L. J. 1979Transport of protein-bound steroid hormones into liver in vivoAm. J. Physiol.237E367E372PubMedGoogle Scholar
  18. 18.
    Valencia, J. V., Weldon, S. C., Quinn, D., Kiers, G. H., DeGroot, J., TeKoppele, J. M., Hughes, T. E. 2004Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kineticsAnal. Biochem.3246878PubMedCrossRefGoogle Scholar
  19. 19.
    Cornford, E. M., Braun, L. D., Pardridge, W. M., Oldendorf, W. H. 1980Blood flow rate and cellular influx of glucose and arginine in mouse liver in vivoAm. J. Physiol.238H553H560PubMedGoogle Scholar
  20. 20.
    Pardridge, W. M., Mietus, L. J. 1982Kinetics of neutral amino acid transport through the blood–brain barrier of the newborn rabbitJ. Neurochem.38955962PubMedGoogle Scholar
  21. 21.
    Yamaoka, K., Tanigawara, Y., Nakagawa, T., Uno, T. 1981A pharmacokinetic analysis program (multi) for microcomputerJ. Pharmacobio-dyn.4879885PubMedGoogle Scholar
  22. 22.
    Seglen, P. O. 1976Preparation of isolated rat liver cellsMethods Cell Biol.132983PubMedGoogle Scholar
  23. 23.
    Liu, F., Song, Y., Liu, D. 1999Hydrodynamics-based transfection in animals by systemic administration of plasmid DNAGene Ther.612581266PubMedCrossRefGoogle Scholar
  24. 24.
    Wakayama, K., Ohtsuki, S., Takanaga, H., Hosoya, K., Terasaki, T. 2002Localization of norepinephrine and serotonin transporter in mouse brain capillary endothelial cellsNeurosci. Res.44173180PubMedCrossRefGoogle Scholar
  25. 25.
    Irizarry, M. C. 2004Biomarkers of Alzheimer disease in plasmaNeuroRx1226234PubMedCrossRefGoogle Scholar
  26. 26.
    Ward, D. M., Kaplan, J. 1990The rate of internalization of different receptor–ligand complexes in alveolar macrophages is receptor-specificBiochem. J.270369374PubMedGoogle Scholar
  27. 27.
    Ward, D. M., Ajioka, R., Kaplan, J. 1989Cohort movement of different ligands and receptors in the intracellular endocytic pathway of alveolar macrophagesJ. Biol. Chem.26481648170PubMedGoogle Scholar
  28. 28.
    Pillot, T., Goethals, M., Vanloo, B., Talussot, C., Brasseur, R., Vandekerckhove, J., Rosseneu, M., Lins, L. 1996Fusogenic properties of the C-terminal domain of the Alzheimer beta-amyloid peptideJ. Biol. Chem.2712875728765PubMedCrossRefGoogle Scholar
  29. 29.
    Jarrett, J. T., Berger, E. P., Lansbury, P. T.,Jr. 1993The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's diseaseBiochemistry3246934697PubMedCrossRefGoogle Scholar
  30. 30.
    Joslin, G., Krause, J. E., Hershey, A. D., Adams, S. P., Fallon, R. J., Perlmutter, D. H. 1991Amyloid-beta peptide, substance P, and bombesin bind to the serpin–enzyme complex receptorJ. Biol. Chem.2662189721902PubMedGoogle Scholar
  31. 31.
    Matter, M. L., Zhang, Z., Nordstedt, C., Ruoslahti, E. 1998The alpha5beta1 integrin mediates elimination of amyloid-beta peptide and protects against apoptosisJ. Cell Biol.14110191030PubMedCrossRefGoogle Scholar
  32. 32.
    Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Bronswijk, W., Martins, R. 2002Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptorJ. Neurosci.22RC221PubMedGoogle Scholar
  33. 33.
    Mackic, J. B., Stins, M., McComb, J. G., Calero, M., Ghiso, J., Kim, K. S., Yan, S. D., Stern, D., Schmidt, A. M., Frangione, B., Zlokovic, B. V. 1998Human blood–brain barrier receptors for Alzheimer's amyloid-beta 1–40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayerJ. Clin. Invest.102734743PubMedGoogle Scholar
  34. 34.
    Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A. M., Armstrong, D. L., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M., Stern, D., Zlokovic, B. 2003RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brainNat. Med.9907913PubMedCrossRefGoogle Scholar
  35. 35.
    Kang, D. E., Pietrzik, C. U., Baum, L., Chevallier, N., Merriam, D. E., Kounnas, M. Z., Wagner, S. L., Troncoso, J. C., Kawas, C. H., Katzman, R., Koo, E. H. 2000Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathwayJ. Clin. Invest.10611591166PubMedGoogle Scholar
  36. 36.
    Bu, G. 2001The roles of receptor-associated protein (RAP) as a molecular chaperone for members of the LDL receptor familyInt. Rev. Cytol.20979116PubMedCrossRefGoogle Scholar
  37. 37.
    Herz, J., Clouthier, D. E., Hammer, R. E. 1992LDL receptor-related protein internalizes and degrades uPA–PAI-1 complexes and is essential for embryo implantationCell71411421PubMedCrossRefGoogle Scholar
  38. 38.
    Willnow, T. E., Armstrong, S. A., Hammer, R. E., Herz, J. 1995Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivoProc. Natl. Acad. Sci. USA9245374541PubMedCrossRefGoogle Scholar
  39. 39.
    Willnow, T. E., Rohlmann, A., Horton, J., Otani, H., Braun, J. R., Hammer, R. E., Herz, J. 1996RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptorsEMBO J.1526322639PubMedGoogle Scholar
  40. 40.
    Rohlmann, A., Gotthardt, M., Hammer, R. E., Herz, J. 1998Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnantsJ. Clin. Invest.101689695PubMedCrossRefGoogle Scholar
  41. 41.
    Pardridge, W. M., Landaw, E. M., Miller, L. P., Braun, L. D., Oldendorf, W. H. 1985Carotid artery injection technique: bounds for bolus mixing by plasma and by brainJ. Cereb. Blood Flow Metab.5576583PubMedGoogle Scholar
  42. 42.
    Schenk, D. 2002Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginningNat. Rev. Neurosci.3824 828PubMedCrossRefGoogle Scholar
  43. 43.
    DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J. C., Paul, S. M., Holtzman, D. M. 2001Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's diseaseProc. Natl. Acad. Sci. USA9888508885PubMedCrossRefGoogle Scholar
  44. 44.
    Wilcock, D. M., Rojiani, A., Rosenthal, A., Subbarao, S., Freeman, M. J., Gordon, M. N., Morgan, D. 2004Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhageJ. Neuroinflammation124PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Chihiro Tamaki
    • 1
  • Sumio Ohtsuki
    • 1
    • 2
    • 3
  • Takeshi Iwatsubo
    • 4
  • Tadafumi Hashimoto
    • 4
  • Kaoru Yamada
    • 4
  • Chiori Yabuki
    • 4
  • Tetsuya Terasaki
    • 1
    • 2
    • 3
  1. 1.Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical SciencesTohoku UniversityAoba-kuJapan
  2. 2.New Industry Creation Hatchery CenterTohoku UniversityAoba-kuJapan
  3. 3.SORST of Japan Science and Technology Agency (JST) Japan
  4. 4.Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical SciencesUniversity of TokyoBunkyokuJapan

Personalised recommendations