Alzheimer's Disease and Dementia Research Unit, Biogen Inc., Cambridge, MA 02142, USA.
Int J Mol Sci. 2019 May 1;20(9):2161. doi: 10.3390/ijms20092161.
Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer's disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to "drug-ability" of this target.
载脂蛋白 E（apoE）是大脑中主要的脂质转运蛋白，主要由星形胶质细胞产生。星形胶质细胞是大脑中数量最多的细胞类型，是神经元的主要支持网络。它们在大脑中胆固醇的合成和运输中发挥着关键作用。人类有三种常见的 apoE 同工型，即 apoE2、apoE3 和 apoE4，它们对散发性和迟发性阿尔茨海默病（AD）的风险和发病年龄具有强烈的基因型效应。携带 ε4 等位基因的个体患 AD 的风险增加，而携带 ε2 等位基因的个体则受到保护。对 apoE 对 AD 发展的贡献的研究得出了相互矛盾的结果，对于该蛋白在疾病中的作用仍有很多推测。在这里，我们回顾了目前文献中描述的对立假设以及被认为是针对 apoE 的新型治疗策略的方法。此外，我们还提供了针对 apoE 进行靶向治疗的基本原理和针对该靶标的“可成药性”带来的挑战的观点。
