Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol
Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol
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DOI：
10.1016/j.bbalip.2010.05.010
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发表时间：
2010-08-01
影响因子：
4.8
通讯作者：
Potier, Marie-Claude
中科院分区：
文献类型：
--
作者：
Cossec, Jack-Christophe;Simon, Anne;Potier, Marie-Claude
一些证据支持胆固醇与阿尔茨海默病发病机制之间的密切关系。已知膜胆固醇可调节淀粉样蛋白前体蛋白（APP）内吞作用和淀粉样蛋白β (A β)分泌。在这里，我们在人类细胞内吞噬模型（HEK293细胞）中显示，胆固醇以剂量依赖性和线性方式在广泛的浓度范围内发挥这些作用（甲基- β -环糊精（MBCD）和MBCD-胆固醇复合物诱导的质膜胆固醇变化分别为-40%至+40%）。我们发现胆固醇的逐渐作用被小干扰rna介导的网格蛋白下调所抑制。利用参与早期内体形成的蛋白突变体（dynamin2、Eps15和Rab5）进一步证实了胆固醇对网格蛋白介导的APP内吞作用的调节。重要的是，我们发现除了APP以外的膜蛋白不受胆固醇的影响。事实上，转铁蛋白和大麻素1受体的网状蛋白依赖内吞作用以及生物素衍生物标记的表面蛋白的内化对质膜胆固醇在-40%到40%之间的变化不敏感。综上所述，网格蛋白依赖性APP内吞作用对膜胆固醇水平非常敏感。这些结果表明，AD患者胆固醇升高可能是APP中clathrin-、dynamin2-、Eps15-和rab5依赖性内吞作用内化增强以及随后A β过量产生的原因。(C) 2010 Elsevier B.V.版权所有
Several lines of evidence support a strong relationship between cholesterol and Alzheimer's disease pathogenesis. Membrane cholesterol is known to modulate amyloid precursor protein (APP) endocytosis and amyloid-beta (A beta) secretion. Here we show in a human cell line model of endocytosis (HEK293 cells) that cholesterol exerts these effects in a dose-dependent and linear manner, over a wide range of concentrations (-40% to +40% variations of plasma membrane cholesterol induced by methyl-beta-cyclodextrin (MBCD) and MBCD-cholesterol complex respectively). We found that the gradual effect of cholesterol is inhibited by small interference RNA-mediated downregulation of clathrin. Modulation of clathrin-mediated APP endocytosis by cholesterol was further demonstrated using mutants of proteins involved in the formation of early endosomes (dynamin2, Eps15 and Rab5). Importantly we show that membrane proteins other than APP are not affected by cholesterol to the same extent Indeed clathrin-dependent endocytosis of transferrin and cannabinoid1 receptors as well as internalization of surface proteins labelled with a biotin derivative (sulfo-NHS-SS-biotin) were not sensitive to variations of plasma membrane cholesterol from -40% to 40%. In conclusion clathrin-dependent APP endocytosis appears to be very sensitive to the levels of membrane cholesterol. These results suggest that cholesterol increase in AD could be responsible for the enhanced internalization of clathrin-, dynamin2-, Eps15- and Rab5-dependent endocytosis of APP and the ensuing overproduction of A beta. (C) 2010 Elsevier B.V. All rights reserved.