Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function.
Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function.
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DOI：
10.1074/jbc.m109.014464
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发表时间：
2009-10-02
期刊：
影响因子：
--
通讯作者：
Weisgraber KH
中科院分区：
文献类型：
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作者：
Zhong N;Ramaswamy G;Weisgraber KH
域相互作用是载脂蛋白 E4 (apoE4) 的一种结构特性，预计有助于 apoE4 与阿尔茨海默病的关联。 Arg-61 apoE 小鼠是一种针对结构域相互作用的基因靶向小鼠模型，其大脑 apoE 水平较低，且存在突触、功能和认知缺陷。我们假设结构域相互作用会引起星形胶质细胞中的内质网 (ER) 应激和针对 Arg-61 apoE 降解的未折叠蛋白反应。原代Arg-61 apoE星形胶质细胞的胞内apoE比野生型星形胶质细胞少，并且未折叠蛋白反应标记物OASIS（老星形胶质细胞特异性诱导物质）、ATF4和XBP-1及下游效应子上调。 ER 应激似乎会导致整体星形胶质细胞功能障碍，因为 Arg-61 apoE 星形胶质细胞的葡萄糖摄取减少，并且在 Neuro-2a 细胞培养物中，星形胶质细胞条件培养基促进神经突生长的效率低于野生型培养基。我们发现 Arg-61 apoE 小鼠大脑 OASIS 水平和加工过程存在年龄依赖性上调。 ER 应激和星形胶质细胞功能障碍代表了 apoE4 与神经退行性疾病关联的新范例。
Domain interaction, a structural property of apolipoprotein E4 (apoE4), is predicted to contribute to the association of apoE4 with Alzheimer disease. Arg-61 apoE mice, a gene-targeted mouse model specific for domain interaction, have lower brain apoE levels and synaptic, functional, and cognitive deficits. We hypothesized that domain interaction elicits an endoplasmic reticulum (ER) stress in astrocytes and an unfolded protein response that targets Arg-61 apoE for degradation. Primary Arg-61 apoE astrocytes had less intracellular apoE than wild-type astrocytes, and unfolded protein response markers OASIS (old astrocyte specifically induced substance), ATF4, and XBP-1 and downstream effectors were up-regulated. ER stress appears to cause global astrocyte dysfunction as glucose uptake was decreased in Arg-61 apoE astrocytes, and astrocyte-conditioned medium promoted neurite outgrowth less efficiently than wild-type medium in Neuro-2a cell cultures. We showed age-dependent up-regulation of brain OASIS levels and processing in Arg-61 apoE mice. ER stress and astrocyte dysfunction represent a new paradigm underlying the association of apoE4 with neurodegeneration.