RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease (original) (raw)

Abstract

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.

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Acknowledgments

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

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Authors and Affiliations

  1. Department of Clinical Neurosciences, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
    John E. Donahue, Stephanie L. Flaherty, Conrad E. Johanson, John A. Duncan III, Miles C. Miller, Rosemarie Tavares, Qian Wu & Edward G. Stopa
  2. Department of Neurosurgery, Stanford University Medical Center and School of Medicine, Stanford, CA, USA
    Gerald D. Silverberg
  3. Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
    Wentian Yang
  4. Molecular Pathology Core, COBRE CCRD, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
    Edmond Sabo
  5. Core Image Analysis Laboratory, Rhode Island Hospital, Providence, RI, USA
    Virginia Hovanesian
  6. Division of Neuropathology, Department of Pathology, Rhode Island Hospital, 593 Eddy Street (APC 12115), Providence, RI, 02903, USA
    John E. Donahue

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  1. John E. Donahue
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  2. Stephanie L. Flaherty
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  3. Conrad E. Johanson
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  4. John A. Duncan III
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  5. Gerald D. Silverberg
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  6. Miles C. Miller
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  7. Rosemarie Tavares
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  8. Wentian Yang
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  9. Qian Wu
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  10. Edmond Sabo
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  11. Virginia Hovanesian
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  12. Edward G. Stopa
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Correspondence toJohn E. Donahue.

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Donahue, J.E., Flaherty, S.L., Johanson, C.E. et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease.Acta Neuropathol 112, 405–415 (2006). https://doi.org/10.1007/s00401-006-0115-3

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