Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene
Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene
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DOI：
10.1385/jmn:23:3:225
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Lahiri, DK
中科院分区：
文献类型：
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作者：
Lahiri, DK
阿尔茨海默病 (AD) 是最常见的痴呆症，是一种进行性、退行性的中枢神经系统疾病。 AD 的主要特征包括选择性神经元细胞死亡以及淀粉样蛋白沉积和神经原纤维缠结的存在。载脂蛋白 E (ApoE) 也已被证明与这些神经病理病变共存。这里回顾一下ApoE在AD中的作用。人类 ApoE 基因具有三个等位基因（epsilon2、epsilon3、epsilon4）——都是同一基因的产物。 epsilon3等位基因占ApoE基因库的大部分（大约70-80%），epsilon4等位基因占10-15%，epsilon2等位基因占5-10%。 epsilon4 等位基因的遗传会大大增加早期患 AD 的风险。 ApoE 的功能包括胆固醇转运、神经元修复、树突生长和抗炎活性。 ApoE-epsilon4 的假定病理功能或“危险因素活动”包括其促进淀粉样蛋白积累、神经毒性、氧化应激和神经原纤维缠结的作用。ApoE mRNA 在肝脏中最丰富，其次是大脑，主要由星形胶质细胞合成和分泌。在人类皮质和海马神经元中进一步检测到 ApoE 蛋白和 mRNA。 ApoE 基因表达是由一些神经元的脑损伤诱导的，并在衰老过程中在星形胶质细胞中上调。在 AD 中，海马体中 ApoE rnRNA 增加。据报道，AD 风险与 ApoE 基因的转录活性相关。 ApoE 启动子中存在推定转录因子 (TF)（例如 AP-1、AP-2 和 NF-kappaB）的结合位点。该启动子还包含炎症反应转录因子 IL-6 RE-BP、MEDI、STAT1 和 STAT2 位点。在 ApoE/ApoCI 基因间区域检测到功能性过氧化物酶体增殖物激活受体 γ (PPARgamma)。 ApoE mRNA 水平受 PPARgamma 诱导剂环格列酮调节。某些他汀类药物也可能影响 ApoE 启动子活性 确定了巨噬细胞中指定 ApoE 基因表达的两个远端增强子。这些结果对 ApoE 基因表达的调控具有重要意义，而 ApoE 基因表达在 AD 的发展中发挥着重要作用。不同转录因子与 ApoE 基因调控区域的相互作用对于了解 AD 中的神经炎症过程非常重要。因此，这些调控位点可能成为控制 ApoE 基因表达的有效药物靶点。
Alzheimer's disease (AD), the most common form of dementia, is a progressive, degenerative disorder of the central nervous system. The major hallmarks of AD include selective neuronal cell death and the presence of amyloid deposits and neurofibrillary tangles. Apolipoprotein E (ApoE) has also been shown to colocalize with these neuropathological lesions. Here is reviewed the role of ApoE in AD. The human ApoE gene has three alleles (epsilon2, epsilon3, epsilon4)-all products of the same gene. The epsilon3-allele accounts for the majority of the ApoE gene pool (similar to70-80%), the epsilon4-allele accounts for 10-15% and the epsilon2 allele for 5-10%. Inheritance of the epsilon4-allele strongly increases the risk for developing AD at an earlier age. Functions of ApoE include cholesterol transport, neuronal repair, dendritic growth and anti-inflammatory activities. Putative pathological functions or "risk-factor activities" of ApoE-epsilon4 include its role in promoting amyloid accumulation, neurotoxicity, oxidative stress and neurofibrillary tangles.ApoE mRNA is most abundant in the liver followed by the brain, where it is synthesized and secreted primarily by astrocytes. ApoE protein and mRNA are further detected in cortical and hippocampal neurons in humans. ApoE gene expression is induced by brain injury in some neurons and upregulated in astrocytes during aging. In AD, an increased ApoE rnRNA was reported in the hippocampus. The risk for AD has been reported to correlate with transcriptional activity of the ApoE gene. Binding sites for putative transcriptional factors (TF), such as AP-1, AP-2 and NF-kappaB, are present in the ApoE promoter. The promoter also contains sites for the inflammatory response transcription factors IL-6 RE-BP, MEDI, STAT1 and STAT2. A functional peroxisome-proliferator-activated receptor gamma (PPARgamma) has been detected in the ApoE/ApoCI intergenic region. ApoE mRNA levels were shown to be regulated by ciglitazone, a PPARgamma inducer. Certain statin drugs may also affect ApoE promoter activity Two distal enhancers that specify ApoE gene expression in macrophages were identified. These results have implications for the regulation of ApoE gene expression, which plays an important role in the development of AD. The interaction of different transcription factors with the regulatory region of the ApoE gene is important to understand the neuroinflammatory process seen in AD. Thus, these regulatory sites can potentially be effective drug targets to control the expression of the ApoE gene.