Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease
Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease
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DOI：
10.1074/jbc.m110.151084
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Mahley, Robert W.
中科院分区：
文献类型：
--
作者：
Chen, Hung-Kai;Ji, Zhong-Sheng;Mahley, Robert W.
载脂蛋白E4是晚发性阿尔茨海默病（AD）的主要遗传危险因子。ApoE 4通过氨基端结构域中的Arg-61和羧基端结构域中的Glu-255介导的分子内相互作用（称为apoE 4结构域相互作用）呈现病理构象。由于AD与线粒体功能障碍有关，我们研究了apoE 4结构域相互作用对线粒体呼吸功能的影响。在从神经元特异性烯醇化酶启动子驱动的apoE 3（NSE-apoE 3）或apoE 4（NSEapoE 4）转基因小鼠的脑皮质培养的神经元中检查线粒体呼吸复合物的稳态量。与NSE apoE 3神经元相比，NSE apoE 4神经元中评估的线粒体呼吸复合物的所有亚基均显著降低。然而，没有显着差异的线粒体复合物的水平之间检测到星形胶质细胞表达不同的载脂蛋白E亚型驱动的胶质细胞酸性蛋白启动子，导致我们的结论，apoE 4的影响是神经元特异性的。在神经母细胞瘤Neuro-2A（N2 A）细胞中，apoE 4表达降低了线粒体呼吸复合物I、IV和V的水平。复合物IV的酶活性也降低，降低了线粒体呼吸能力。缺乏结构域相互作用的突变体apoE 4（apoE 4-Thr-61）在N2 A细胞中不诱导线粒体功能障碍，表明该作用对apoE 4表达细胞是特异性的，并且依赖于结构域相互作用。与这一发现一致，用破坏apoE 4结构域相互作用的小分子处理apoE 4表达N2 A细胞恢复了线粒体呼吸复合物IV水平。这些结果表明，药物干预与小分子，破坏apoE 4结构域的相互作用是一个潜在的治疗方法apoE 4携带AD受试者。
Apolipoprotein (apo) E4 is the major genetic risk factor for late-onset Alzheimer disease (AD). ApoE4 assumes a pathological conformation through an intramolecular interaction mediated by Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain, referred to as apoE4 domain interaction. Because AD is associated with mitochondrial dysfunction, we examined the effect of apoE4 domain interaction on mitochondrial respiratory function. Steady-state amounts of mitochondrial respiratory complexes were examined in neurons cultured from brain cortices of neuron-specific enolase promoter-driven apoE3 (NSE-apoE3) or apoE4 (NSEapoE4) transgenic mice. All subunits of mitochondrial respiratory complexes assessed were significantly lower in NSEapoE4 neurons compared with NSE-apoE3 neurons. However, no significant differences in levels of mitochondrial complexes were detected between astrocytes expressing different apoE isoforms driven by the glial fibrillary acidic protein promoter, leading to our conclusion that the effect of apoE4 is neuron specific. In neuroblastoma Neuro-2A (N2A) cells, apoE4 expression reduced the levels of mitochondrial respiratory complexes I, IV, and V. Complex IV enzymatic activity was also decreased, lowering mitochondrial respiratory capacity. Mutant apoE4 ( apoE4-Thr-61) lacking domain interaction did not induce mitochondrial dysfunction in N2A cells, indicating that the effect is specific to apoE4-expressing cells and dependent on domain interaction. Consistent with this finding, treatment of apoE4-expressing N2A cells with a small molecule that disrupts apoE4 domain interaction restored mitochondrial respiratory complex IV levels. These results suggest that pharmacological intervention with small molecules that disrupt apoE4 domain interaction is a potential therapeutic approach for apoE4-carrying AD subjects.