Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
复制标题
DOI：
10.1101/cshperspect.a006312
复制
发表时间：
2012-03-01
影响因子：
5.4
通讯作者：
Bu, Guojun
中科院分区：
文献类型：
--
作者：
Holtzman, David M.;Herz, Joachim;Bu, Guojun
载脂蛋白E （APOE）基因型是阿尔茨海默病（AD）的主要遗传危险因素；4等位基因增加风险而2等位基因具有保护作用。在中枢神经系统（CNS）中，apoE由胶质细胞产生，存在于高密度样脂蛋白中，与低密度脂蛋白受体（LDLR）家族的几个受体相互作用，并且是一种与淀粉样蛋白- β (a β)肽结合的蛋白质。载脂蛋白e异构体影响AD风险的机制多种多样。有大量证据表明，apoE亚型对AD风险的不同影响受apoE影响大脑中A β聚集和清除的能力的影响。其他机制也可能在apoE影响中枢神经系统功能和AD的能力中发挥作用，包括对突触可塑性、细胞信号、脂质转运和代谢以及神经炎症的影响。ApoE受体，包括LDLRs、Apoer2、极低密度脂蛋白受体（VLDLRs）和脂蛋白受体相关蛋白1 （LRP1）似乎既影响ApoE的中枢神经系统作用，也影响A β代谢和毒性。基于apoE和apoE受体的治疗策略可能包括影响apoE/A β相互作用、apoE结构、apoE脂化、LDLR受体家族成员功能和信号传导。了解apoE、apoE受体和AD之间的正常和疾病相关生物学关系，可能为AD的发病机制和治疗提供新的见解。
Apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer disease (AD); the epsilon 4 allele increases risk and the epsilon 2 allele is protective. In the central nervous system (CNS), apoE is produced by glial cells, is present in high-density-like lipoproteins, interacts with several receptors that are members of the low-density lipoprotein receptor (LDLR) family, and is a protein that binds to the amyloid-beta (A beta) peptide. There are a variety of mechanisms by which apoE isoform may influence risk for AD. There is substantial evidence that differential effects of apoE isoform on AD risk are influenced by the ability of apoE to affect A beta aggregation and clearance in the brain. Other mechanisms are also likely to play a role in the ability of apoE to influence CNS function as well as AD, including effects on synaptic plasticity, cell signaling, lipid transport and metabolism, and neuroinflammation. ApoE receptors, including LDLRs, Apoer2, very low-density lipoprotein receptors (VLDLRs), and lipoprotein receptor-related protein 1 (LRP1) appear to influence both the CNS effects of apoE as well as A beta metabolism and toxicity. Therapeutic strategies based on apoE and apoE receptors may include influencing apoE/A beta interactions, apoE structure, apoE lipidation, LDLR receptor family member function, and signaling. Understanding the normal and disease-related biology connecting apoE, apoE receptors, and AD is likely to provide novel insights into AD pathogenesis and treatment.