Vance Jean E, Hayashi Hideki
Group on Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Biochim Biophys Acta. 2010 Aug;1801(8):806-18. doi: 10.1016/j.bbalip.2010.02.007. Epub 2010 Feb 17.
The strongest known genetic risk factor for the development of late-onset Alzheimer disease is inheritance of the apolipoprotein (apo) E4 (epsilon4 allele) although the mechanisms underlying this connection are still not entirely clear. In this review, we shall discuss the role of apo E in the brain, particularly in relation to Alzheimer disease. Cholesterol transport and homeostasis in the central nervous system (CNS) are separated from that in the peripheral circulation by the blood-brain barrier. However, the brain operates its own lipoprotein transport system that is mediated by high density lipoprotein-sized, apo E-containing lipoproteins that are synthesized and secreted by glial cells (primarily astrocytes). Several ATP-binding cassette (ABC) transporters are expressed in the brain, including ABCA1 and ABCG1 which play important roles in the transfer of phospholipids and cholesterol to apo E. The astrocyte-derived apo E-containing lipoproteins can bind to, and be internalized by, receptors of the low density lipoprotein receptor superfamily that are located on the surface of neurons. In addition to these receptors serving as endocytosis receptors for lipoproteins, several of these receptors also act as signaling receptors in neurons and activate pathways involved in axonal growth, as well as neuronal survival. These beneficial pathways appear to be enhanced to a greater extent by apo E3 than by apo E4. Apo E has also been implicated in the deposition of amyloid plaques since apo E3, more readily than apo E4, forms a complex with Ass peptides, and mediates the degradation of amyloid deposits.
已知晚发性阿尔茨海默病发生的最强遗传风险因素是载脂蛋白（apo）E4（ε4等位基因）的遗传，尽管这种关联背后的机制仍不完全清楚。在这篇综述中，我们将讨论apo E在大脑中的作用，特别是与阿尔茨海默病相关的作用。中枢神经系统（CNS）中的胆固醇转运和稳态通过血脑屏障与外周循环中的胆固醇转运和稳态相分离。然而，大脑有自己的脂蛋白转运系统，该系统由神经胶质细胞（主要是星形胶质细胞）合成和分泌的高密度脂蛋白大小、含apo E的脂蛋白介导。几种ATP结合盒（ABC）转运蛋白在大脑中表达，包括ABCA1和ABCG1，它们在将磷脂和胆固醇转移到apo E中起重要作用。星形胶质细胞衍生的含apo E的脂蛋白可以与位于神经元表面的低密度脂蛋白受体超家族的受体结合并被其内化。除了这些作为脂蛋白内吞受体的受体外，其中一些受体还在神经元中充当信号受体，并激活参与轴突生长以及神经元存活的途径。这些有益途径似乎在更大程度上被apo E3增强而不是被apo E4增强。apo E也与淀粉样斑块的沉积有关，因为apo E3比apo E4更容易与Aβ肽形成复合物，并介导淀粉样沉积物的降解。
