Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany.
J Neurosci. 2013 Jan 2;33(1):358-70. doi: 10.1523/JNEUROSCI.2425-12.2013.
Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β (Aβ) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
载脂蛋白 E（APOE）是散发性阿尔茨海默病的主要风险因素。除其他功能外，APOE 被提议将神经毒性淀粉样β（Aβ）肽在大脑中隔离，并通过神经元 APOE 受体将其递送至细胞分解代谢。然而，参与此过程的受体仍存在争议。在这里，我们确定了前神经营养素受体 sortilin 是神经元中清除 APOE/Aβ 复合物的主要内吞途径。Sortilin 与 APOE 具有高亲和力结合。在小鼠中缺乏受体表达会导致 APOE 和 Aβ在大脑中的积累，并加重斑块负担。此外，尽管其他 APOE 受体表达正常，但缺乏 sortilin 的原代神经元摄取 APOE/Aβ 复合物的能力明显受损。尽管脑 APOE 水平高于正常，但缺乏 sortilin 的动物表现出脑脂质代谢异常（例如，硫酸盐积累），这在 APOE 缺乏的小鼠中可见，表明细胞 APOE 摄取途径存在功能缺陷。总之，我们的研究结果确定了 sortilin 作为体内载脂蛋白 E 脂蛋白的必需神经元途径，并提示 Aβ 分解代谢和前神经营养素信号之间存在有趣的联系，该信号集中在该受体上。
