Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing
Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing
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DOI：
10.1016/j.bbamem.2010.10.014
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发表时间：
2011-01-01
影响因子：
3.4
通讯作者：
Koegel, Donat
中科院分区：
文献类型：
--
作者：
Eckert, Gunter P.;Chang, Steffi;Koegel, Donat
神经元膜的流动性在脑老化和神经退行性变中起着关键作用。在这项研究中，我们研究了ω-3脂肪酸二十二碳六烯酸（DHA）在调节膜流动性中的作用。APP加工和保护免受细胞毒性应激。为此，我们应用单层转移脂质体，其提供保护免受氧化并有效地将DHA掺入细胞膜中。脂质体转移二十二烷酸（DA），完全饱和形式的DHA，细胞培养物作为对照。在HEK-APP细胞中，DHA显著增加了膜流动性和APP的非淀粉样蛋白加工，导致sAPP α分泌增强。这种增强的sAPP α分泌与对ER Ca 2+库耗竭诱导的细胞凋亡的实质性保护相关。从HEK-APP细胞获得的含有sAPP α的上清液在神经元PC 12细胞和HEK 293对照细胞中发挥与DHA类似的保护作用。与进一步增加的sAPP α水平相关，从DHA处理的HEK-APP细胞获得的上清液增强了保护作用，而从DHA处理的HEK 293对照细胞获得的上清液没有抑制细胞凋亡，这可能是由于这些细胞中内源性APP的低表达和可忽略的sAPP α分泌。用小分子抑制剂LY 294002和SP 600125的进一步实验表明，sAPP α诱导的细胞保护依赖于抗凋亡PI 3 K/Akt通路的激活和应激触发的JNK信号通路的抑制。我们的数据表明，脂质体DHA能够恢复或维持生理膜特性，这是神经保护性sAPP α分泌和神经元存活的自分泌调节所必需的。(C)2010爱思唯尔有限公司版权所有。
The fluidity of neuronal membranes plays a pivotal role in brain aging and neurodegeneration. In this study, we investigated the role of the omega-3 fatty acid docosahexaenoic acid (DHA) in modulation of membrane fluidity. APP processing, and protection from cytotoxic stress. To this end, we applied unilamellar transfer liposomes, which provided protection from oxidation and effective incorporation of DHA into cell membranes. Liposomes transferring docosanoic acid (DA), the completely saturated form of DHA, to the cell cultures served as controls. In HEK-APP cells, DHA significantly increased membrane fluidity and non-amyloidogenic processing of APP, leading to enhanced secretion of sAPP alpha. This enhanced secretion of sAPP alpha was associated with substantial protection against apoptosis induced by ER Ca2+ store depletion. sAPP alpha-containing supernatants obtained from HEK-APP cells exerted similar protective effects as DHA in neuronal PC12 cells and HEK293 control cells. Correlating to further increased sAPP alpha levels, supernatants obtained from DHA-treated HEK-APP cells enhanced protection, whereas supernatants obtained from DHA-treated HEK293 control cells did not inhibit apoptosis, likely due to the low expression of endogenous APP and negligible sAPP alpha secretion in these cells. Further experiments with the small molecule inhibitors LY294002 and SP600125 indicated that sAPP alpha-induced cytoprotection relied on activation of the anti-apoptotic PI3K/Akt pathway and inhibition of the stress-triggered JNK signaling pathway in PC12 cells. Our data suggest that liposomal DHA is able to restore or maintain physiological membrane properties, which are required for neuroprotective sAPP alpha secretion and autocrine modulation of neuronal survival. (C) 2010 Elsevier B.V. All rights reserved.