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| γ分泌酶活性的抑制降低了Aβ的产生，减少了氧化应激，增强了线粒体活性，并导致细胞凋亡易感性的降低：对治疗阿尔茨海默病的影响 |
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| Inhibition of γ-secretase activity reduces Aβ production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: Implications for the treatment of Alzheimer's disease |
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| Sheng B., Gong K., Niu Y., Liu L., Yan Y., Lu G., Zhang L., Hu M., Zhao N., Zhang X., Tang P., Gong Y. 2009/5/29 18:38:57 |
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Free Radical Biology and Medicine, 2009, Volume 46, Issue 10
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| It has been argued that γ-secretase should be considered as a pharmacological target, as there are few mechanism-based experimental and clinical studies on γ-secretase treatment. In this study, we found that N2a cells bearing APP695 or its Swedish mutant exhibited increased basal levels of ROS, nitric oxide (NO), protein carbonyls, MDA and intracellular calcium, as well as reduced level of the mitochondrial membrane potential and ATP. When the activity of γ-secretase was inhibited by expression of the D385A PS1 variant, cells (N2a/Swe.D385A) showed reduced basal levels of ROS, nitric oxide (NO), protein carbonyls, MDA and intracellular calcium, as well as increased mitochondrial membrane potential and ATP level. In addition, N2a/Swe.D385A cells showed reduced vulnerability to H2O2-induced apoptosis. The Bcl-2 and JNK/ERK pathways were proven to be involved in the change of vulnerability to H2O2-induced apoptosis. Moreover, we discovered that inhibition of γ-secretase by DAPT would lead to a reduction of ROS levels and stabilization of mitochondrial function in APP (N2a/APP695) and APP Swedish mutant (N2a/APPswe) transfected cells. At last, it was shown that Aβ antibody and antiserum prevented increase of ROS and reduction of mitochondrial membrane potential in N2a/Swe.ΔE9 cells but not in N2a/Swe.D385A cells, which indicated that reduced formation of Aβ was the reason for reduction of ROS formation and increase of mitochondrial membrane potential when PS-1 activity was impaired in N2a/Swe.D385A cells. We concluded that neurotoxicity was positively correlated with the activity of γ-secretase, which suggested inhibition of γ-secretase is a rational pharmacological target for Alzheimer's disease treatment. © 2009 Elsevier Inc. All rights reserved. |
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| Correspondence Address: Gong, Y.; State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, 100084, China; email: gongyd@tsinghua.edu.cn |
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 疾病资源中心
王燕燕 王曙
上海交通大学附属瑞金医院内分泌科
患者，女，69岁。2009年1月无明显诱因下出现乏力，当时程度较轻，未予以重视。2009年3月患者乏力症状加重，尿色逐渐加深，大便习惯改变，颜色变淡。4月18日入我院感染科治疗，诉轻度头晕、心慌，体重减轻10kg。无肝区疼痛，无发热，无腹痛、腹泻、腹胀、里急后重，无恶性、呕吐等。入院半月前于外院就诊，查肝功能：ALT 601IU/L，AST 785IU/L，TBIL 97.7umol/L，白蛋白 41g/L，甲状腺功能：游离T3 30.6pmol/L，游离T4 51.9pmol/L，心电图示快速房颤。
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