Acta Neuropathologica

, Volume 112, Issue 4, pp 405–415 | Cite as

RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease

  • John E. Donahue
  • Stephanie L. Flaherty
  • Conrad E. Johanson
  • John A. Duncan III
  • Gerald D. Silverberg
  • Miles C. Miller
  • Rosemarie Tavares
  • Wentian Yang
  • Qian Wu
  • Edmond Sabo
  • Virginia Hovanesian
  • Edward G. Stopa
Original Paper


The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of β-amyloid across the blood–brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of β-amyloid out of the brain. To determine whether there are Alzheimer’s disease (AD)-related changes in these BBB-associated β-amyloid receptors, we studied RAGE, LRP-1, and β-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and β-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and β-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.


Alzheimer’s disease Blood–brain barrier Amyloid-β-protein Receptor for advanced glycation end products Low-density lipoprotein receptor-related protein-1 



The authors wish to thank Tien Nguyen, Frederick Goulette, Anthony Spangenberger, and Mirna Lechpammer for their contributions in the preparation of this manuscript, as well as the Harvard Brain Tissue Resource Center (supported in part by PHS grant #R24MH068855) for supplying some of the tissues used in the experiments. The Rae and Jerry Richter Alzheimer’s disease research fund also provided support for this manuscript


  1. 1.
    (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease The National Institute on Aging, and Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer’s disease. Neurobiol Aging 18:S1–2Google Scholar
  2. 2.
    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259CrossRefGoogle Scholar
  3. 3.
    Cras P, Kawai M, Siedlak S, Mulvihill P, Gambetti P, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G (1990) Neuronal and microglial involvement in beta-amyloid protein deposition in Alzheimer’s disease. Am J Pathol 137:241–246PubMedGoogle Scholar
  4. 4.
    Cummings BJ, Su JH, Geddes JW, Van Nostrand WE, Wagner SL, Cunningham DD, Cotman CW (1992) Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer’s disease. Neuroscience 48:763–777PubMedCrossRefGoogle Scholar
  5. 5.
    D’Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH (2001) Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s disease. Histopathology 38:120–134PubMedCrossRefGoogle Scholar
  6. 6.
    Deane R, Du YS, Submamaryan R, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt A, Armstrong D, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. Nat Med 9:907–913PubMedCrossRefGoogle Scholar
  7. 7.
    Grimsley PG, Quinn KA, Chesterman CN, Owensby DA (1999) Evolutionary conservation of circulating soluble low density lipoprotein receptor-related protein-like (“LRP-like”) molecules. Thromb Res 94:153–164PubMedCrossRefGoogle Scholar
  8. 8.
    Harris-White ME, Frautschy SA (2005) Low density lipoprotein receptor-related proteins (LRPs), Alzheimer’s and cognition. Curr Drug Targets CNS Neurol Disord 4:469–480PubMedCrossRefGoogle Scholar
  9. 9.
    Herz J, Marschang P (2003) Coaxing the LDL receptor family into the fold. Cell 112:289–292PubMedCrossRefGoogle Scholar
  10. 10.
    Mackic J, Stins M, McComb J, Calero M, Ghiso J, Kim K, Yan S, Stern D, Schmidt A, Frangione B, Zlokovic B (1998) Human 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 monolayer. J Clin Invest 102:734–743PubMedCrossRefGoogle Scholar
  11. 11.
    Monro OR, Mackic JB, Yamada S, Segal MB, Ghiso J, Maurer C, Calero M, Frangione B, Zlokovic BV (2002) Substitution at codon 22 reduces clearance of Alzheimer’s amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol Aging 23:405–412PubMedCrossRefGoogle Scholar
  12. 12.
    Pluta R, Barcikowska M, Januszewski S, Misicka A, Lipkowski A (1996) Evidence of blood–brain barrier permeability/leakage for circulating human Alzheimer’s beta-amyloid-(1–42)-peptide. Neuroreport 7:1261–1265PubMedGoogle Scholar
  13. 13.
    Poduslo J, Curran G, Sanyal B, Selkoe D (1999) Receptor-mediated transport of human amyloid beta-protein 1–40 and 1–42 at the blood–brain barrier. Neurobiol Dis 6:190–199PubMedCrossRefGoogle Scholar
  14. 14.
    Powers J, Skeen J (1988) Ultrastructural heterogeneity in cerebral amyloid of Alzheimer’s disease. Acta Neuropathol (Berl) 76:613–623CrossRefGoogle Scholar
  15. 15.
    Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11:575–580PubMedCrossRefGoogle Scholar
  16. 16.
    Rubenstein E (1998) Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the aged. Lancet 351:283–285PubMedCrossRefGoogle Scholar
  17. 17.
    Sasaki N, Toki S, Chowei H, Saito T, Nakano N, Hayashi Y, Takeuchi M, Makita Z (2001) Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease. Brain Res 888:256–262PubMedCrossRefGoogle Scholar
  18. 18.
    Selkoe DJ (1989) Molecular pathology of amyloidogenic proteins and the role of vascular amyloidosis in Alzheimer’s disease. Neurobiol Aging 10:387–395PubMedCrossRefGoogle Scholar
  19. 19.
    Selkoe DJ (2000) Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 924:17–25PubMedCrossRefGoogle Scholar
  20. 20.
    Shibata M, Yamada S, Kumar S, Calero M, Bading J, Frangione B, Holtzman D, Miller C, Strickland D, Ghiso J, Zlokovic B (2000) 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 106:1489–1499PubMedGoogle Scholar
  21. 21.
    Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD, Bronte-Stewart H, Rubenstein E, Possin K, Saul TA (2001) The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 57:1763–1766PubMedGoogle Scholar
  22. 22.
    Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D (2003) Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol 2:506–511PubMedCrossRefGoogle Scholar
  23. 23.
    Siman R, Card JP, Nelson RB, Davis LG (1989) Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3:275–285PubMedCrossRefGoogle Scholar
  24. 24.
    Stewart PA, Hayakawa K, Akers MA, Vinters HV (1992) A morphometric study of the blood–brain barrier in Alzheimer’s disease. Lab Invest 67:734–742PubMedGoogle Scholar
  25. 25.
    Tooyama I, Kawamata T, Akiyama H, Kimura H, Moestrup SK, Gliemann J, Matsuo A, McGeer PL (1995) Subcellular localization of the low density lipoprotein receptor-related protein (alpha 2-macroglobulin receptor) in human brain. Brain Res 691:235–238PubMedCrossRefGoogle Scholar
  26. 26.
    Wolf BB, Lopes MB, VandenBerg SR, Gonias SL (1992) Characterization and immunohistochemical localization of alpha 2-macroglobulin receptor (low-density lipoprotein receptor-related protein) in human brain. Am J Pathol 141:37–42PubMedGoogle Scholar
  27. 27.
    Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691PubMedCrossRefGoogle Scholar
  28. 28.
    Yan SD, Stern D, Kane MD, Kuo YM, Lampert HC, Roher AE (1998) RAGE-Abeta interactions in the pathophysiology of Alzheimer’s disease. Restor Neurol Neurosci 12:167–173PubMedGoogle Scholar
  29. 29.
    Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D, Kindy M (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 6:643–651PubMedCrossRefGoogle Scholar
  30. 30.
    Zerbinatti CV, Bu G (2005) LRP and Alzheimer’s disease. Rev Neurosci 16:123–135PubMedGoogle Scholar
  31. 31.
    Zlokovic B (1997) Can blood–brain barrier play a role in the development of cerebral amyloidosis and Alzheimer’s disease pathology. Neurobiol Dis 4: 23–26PubMedCrossRefGoogle Scholar
  32. 32.
    Zlokovic BV (2004) Clearing amyloid through the blood–brain barrier. J Neurochem 89:807–811PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • John E. Donahue
    • 1
    • 6
  • Stephanie L. Flaherty
    • 1
  • Conrad E. Johanson
    • 1
  • John A. Duncan III
    • 1
  • Gerald D. Silverberg
    • 2
  • Miles C. Miller
    • 1
  • Rosemarie Tavares
    • 1
  • Wentian Yang
    • 3
  • Qian Wu
    • 1
  • Edmond Sabo
    • 4
  • Virginia Hovanesian
    • 5
  • Edward G. Stopa
    • 1
  1. 1.Department of Clinical Neurosciences Rhode Island Hospital and Brown Medical SchoolProvidenceUSA
  2. 2.Department of NeurosurgeryStanford University Medical Center and School of MedicineStanfordUSA
  3. 3.Cancer Biology Program, Division of Hematology-Oncology, Department of MedicineBeth Israel-Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  4. 4.Molecular Pathology Core, COBRE CCRDRhode Island Hospital and Brown Medical SchoolProvidenceUSA
  5. 5.Core Image Analysis LaboratoryRhode Island HospitalProvidenceUSA
  6. 6.Division of Neuropathology, Department of PathologyRhode Island HospitalProvidenceUSA

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