摘要 : 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 (Abet... 展开 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_(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 Abeta_(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 Abeta_(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 Abeta_(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 Abeta_(42)-induced ROS production and the colocaliza-tion 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_(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 cPI_A_2 phosphorylation in primary astrocytes. Therefore, this study demonstrates that NADPH oxidase complex assembly and ROS production are not required for Abeta_(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. Published by Elsevier Ltd on behalf of IBRO. 收起