Role of Aβ-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A 2 activation in astrocytes and cerebral endothelial cells

S. Askarova, X. Yang, W. Sheng, G. Y. Sun, J. C M Lee

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

Abstract

Blood-brain barrier (BBB) dysfunctions have been implicated in the progression of Alzheimer's disease. Cerebral endothelial cells (CECs) and astrocytes are the main cell components of the BBB. Although amyloid-β oligomers (Aβ 42) have been reported to mediate oxidative damage to the CECs and astrocytes and trigger the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, the cell surface binding site for Aβ 42 and exact sequence of these events have yet to be elucidated. In this study, the receptor for advanced glycation endproducts (RAGE) was postulated to function as a signal transducing cell surface receptor for Aβ 42 to induce reactive oxygen species (ROS) generation from NADPH oxidase and trigger downstream pathways for the phosphorylation of extracellular signal-regulated kinases (ERK1/2) and cytosolic phospholipase A 2 (cPLA 2). We found that Aβ 42 competed with the anti-RAGE antibody (Ab RAGE) to bind to RAGE on the surfaces of CECs and primary astrocytes. In addition, Ab RAGE abrogate Aβ 42-induced ROS production and the colocalization between the cytosolic (p47-phox) and membrane (gp91-phox) subunits of NADPH oxidase in both cell types. Ab RAGE as well as NADPH oxidase inhibitor and ROS scavenger suppressed Aβ 42-induced ERK1/2 and cPLA 2 phosphorylation in CECs. At the same time, only Ab RAGE, but neither NADPH oxidase inhibitor nor ROS scavenger, inhibited the ERK1/2 pathway and cPLA 2 phosphorylation in primary astrocytes. Therefore, this study demonstrates that NADPH oxidase complex assembly and ROS production are not required for Aβ 42 binding to RAGE at astrocytic surface leading to sequential phosphorylation of ERK1/2 and cPLA 2, and suggests the presence of two different RAGE-dependent downstream pathways in the CECs and astrocytes.

Original languageEnglish
Pages (from-to)375-385
Number of pages11
JournalNeuroscience
Volume199
DOIs
Publication statusPublished - Dec 29 2011
Externally publishedYes

Keywords

  • CPLA
  • ERK
  • NADPH oxidase
  • RAGE

ASJC Scopus subject areas

  • Neuroscience(all)

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