Role of Aβ-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A₂ activation in astrocytes and cerebral endothelial cells.
Role of Aβ-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A₂ activation in astrocytes and cerebral endothelial cells.
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DOI：
10.1016/j.neuroscience.2011.09.038
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发表时间：
2011-12-29
期刊：
影响因子：
3.3
通讯作者：
Lee, J. C-M
中科院分区：
文献类型：
--
作者：
Askarova, S.;Yang, X.;Sheng, W.;Sun, G. Y.;Lee, J. C-M
血脑屏障（BBB）功能障碍与阿尔茨海默病的发展和进展有关。脑内皮细胞和星形胶质细胞是血脑屏障的主要细胞成分。虽然已报道淀粉样β寡聚体（Aβ42）介导CEC和星形胶质细胞的氧化损伤并触发下游MAPK/ERK通路，但Aβ42的细胞表面结合位点和这些事件的确切序列尚未阐明。在这项研究中，晚期糖基化终末产物受体（receptor for advanced glycation endproducts，ERK）被认为是Aβ42的信号转导细胞表面受体，可诱导NADPH氧化酶产生ROS，并触发细胞外信号调节激酶（extracellular-signal-regulated kinases，ERK 1/2）和胞浆磷酸化酶A2（cPLA 2）磷酸化的下游通路。我们发现，Aβ42与抗β 2-D-半乳糖苷酶抗体（Ab）竞争结合CEC和原代星形胶质细胞表面的β 2-D-半乳糖苷酶。此外，AbRAGE消除了Aβ42诱导的活性氧产生以及两种细胞类型中NADPH氧化酶的胞浆（p47-phox）和膜（gp 91-phox）亚基之间的共定位。ABBYY、NADPH氧化酶抑制剂和ROS清除剂可抑制Aβ42诱导的CEC中ERK 1/2和cPLA 2磷酸化。同时，只有阿贝伐他汀，而不是NADPH氧化酶抑制剂或ROS清除剂，抑制ERK 1/2途径和cPLA 2磷酸化在原代星形胶质细胞。因此，本研究表明，NADPH氧化酶复合物组装和ROS产生不是Aβ42在星形胶质细胞表面与ERK结合导致ERK 1/2和cPLA 2连续磷酸化所必需的，并表明CEC和星形胶质细胞中存在两种不同的RAGE依赖性下游途径。
Blood-brain barrier (BBB) dysfunctions have been implicated in the development and progression of Alzheimer's disease. Cerebral endothelial cells (CECs) and astrocytes are the main cell components of the BBB. Although amyloid-β oligomers (Aβ42) have been reported to mediate oxidative damage to the CECs and astrocytes and trigger the downstream MAPK/ERK pathway, the cell surface binding site for Aβ42 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 Aβ42 to induce ROS generation from NADPH oxidase and trigger downstream pathways for the phosphorylation of extracellular-signal-regulated kinases (ERK1/2) and cytosolic phosphorilase A2 (cPLA2). We found that Aβ42 competed with the anti-RAGE antibody (AbRAGE) to bind to RAGE on the surfaces of CECs and primary astrocytes. In addition, AbRAGE abrogate Aβ42-induced ROS production and the co-localization between the cytosolic (p47-phox) and membrane (gp91-phox) subunits of NADPH oxidase in both cell types. AbRAGE, as well as NADPH oxidase inhibitor and ROS scavenger suppressed Aβ42-induced ERK1/2 and cPLA2 phosphorylation in CECs. At the same time, only AbRAGE, but not NADPH oxidase inhibitor or ROS scavenger, inhibited the ERK1/2 pathway and cPLA2 phosphorylation in primary astrocytes. Therefore, this study demonstrates that NADPH oxidase complex assembly and ROS production are not required for Aβ42 binding to RAGE at astrocytic surface leading to sequential phosphorylation of ERK1/2 and cPLA2, and suggests the presence of two different RAGE-dependent downstream pathways in the CECs and astrocytes.
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影响因子：
5.3
作者：
Hsu, Ming-Jen;Hsu, Chung Y.;Lin, Chien-Huang
通讯作者：
Lin, Chien-Huang
DOI：
10.1098/rstb.2005.1766
发表时间：
2005-12-29
影响因子：
6.3
作者：
Abramov, AY;Duchen, MR
通讯作者：
Duchen, MR
影响因子：
2.1
作者：
Deane, Rashid;Zlokovic, Berislav V.
通讯作者：
Zlokovic, Berislav V.
DOI：
10.1093/jnen/63.7.735
发表时间：
2004-07-01
影响因子：
3.2
作者：
Ervin, JF;Pannell, C;Hulette, CM
通讯作者：
Hulette, CM
影响因子：
2.9
作者：
Kalaria, RN;Pax, AB
通讯作者：
Pax, AB