| First Author | Askarova S | Year | 2011 |
| Journal | Neuroscience | Volume | 199 |
| Pages | 375-85 | PubMed ID | 21978883 |
| Mgi Jnum | J:184039 | Mgi Id | MGI:5319758 |
| Doi | 10.1016/j.neuroscience.2011.09.038 | Citation | Askarova S, et al. (2011) Role of Abeta-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A(2) activation in astrocytes and cerebral endothelial cells. Neuroscience 199:375-85 |
| abstractText | 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-beta oligomers (Abeta(4)(2)) 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 Abeta(4)(2) 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 Abeta(4)(2) 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 Abeta(4)(2) 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 Abeta(4)(2)-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 Abeta(4)(2)-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 Abeta(4)(2) 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. |
