RAGE-aβ interactions in the pathophysiology of Alzheimer's disease

Shi Du Yan, David Stern, Michael D. Kane, Yu Min Kuo, Heather C. Lampert, Alex E. Roher

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Abstract

RAGE is a cell surface molecule primarily identified for its capacity to bind advanced glycation end-products and amphoterin. Immunocytochemical studies demonstrated that in Alzheimer's disease (AD) the expression of RAGE is elevated in neurons close to neuritic plaque beta-amyloid (Aβ) deposits and in the cells of Aβ containing vessels. Cross-linking of surface bound Aβ 1-40 to endothelial cells, yielded a band of 50 kDa identified as RAGE. Using the soluble extracellular domain of recombinant human RAGE, we found that Aβ binds to RAGE with a Kd = 57 ± 14 nM, a value close to those found for mouse brain endothelial cells and rat cortical neurons. The interaction of Aβ with RAGE in neuronal, endothelial, and RAGE-transfected COS-1 cells induced oxidative stress, as assessed by the TBARS and MTT assays. ELISA demonstrated a 2.5 times increase of RAGE in AD over control brains. Activated microglia also showed elevated expression of RAGE. In the BV-2 microglial cell line, RAGE bound Aβ in a dose dependent manner with a Kd of 25 ± 9 nM. Soluble Aβ induced the migration of microglia along a concentration gradient, while immobilized Aβ arrested this migration. Aβ- RAGE interaction also activated NF-κB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that RAGE-Aβ interactions play an important role in the pathophysiology of Alzheimer's disease.

Original languageEnglish
Pages (from-to)167-173
Number of pages7
JournalRestorative Neurology and Neuroscience
Volume12
Issue number2-3
Publication statusPublished - 1998 Jun 1

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All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience
  • Clinical Neurology

Cite this

Yan, S. D., Stern, D., Kane, M. D., Kuo, Y. M., Lampert, H. C., & Roher, A. E. (1998). RAGE-aβ interactions in the pathophysiology of Alzheimer's disease. Restorative Neurology and Neuroscience, 12(2-3), 167-173.