Lukiw W J, Bazan N G
Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112-2272, USA.
Biochem Soc Trans. 2006 Dec;34(Pt 6):1277-82. doi: 10.1042/BST0341277.
Significant advancements in our understanding of cell-survival signalling in AD (Alzheimer's disease) stem from recent investigations into the metabolism, trafficking and fate of the essential omega-3 fatty acid DHA (docosahexaenoic acid) (C(22:6), n=3). Brain synaptic terminals and neuronal plasma membranes are highly enriched in DHA, and deficiencies in this polyunsaturated fatty acid are characteristic of AD-affected brain. Oxidative stress, targeting phospholipids containing DHA, and age-related DHA depletion are associated with the progressive erosion of normal cognitive function in AD. Current studies support the idea that DHA itself and novel DHA-derived neural synapse- and membrane-derived lipid messengers have considerable potential to modulate cell survival signalling in stressed cultured neural cell models in vitro and in mammalian models of learning, memory and AD in vivo. Key players in this intrinsic rescue system include the alpha-secretase-processed neurotrophin sAPPalpha [soluble APPalpha (amyloid precursor protein alpha)] peptide, the DHA-derived 10,17S-docosatriene NPD1 (neuroprotectin D1), a tandem brain cytosolic phospholipase A(2) and 15-lipoxygenase enzymatic system that biosynthesizes NPD1, and a small family of anti-apoptotic neuroprotective genes that encode Bcl-2, Bcl-X(L) and Bfl-1 (A1). This paper reviews current ideas regarding DHA and the oxygenated DHA derivative NPD1, intrinsically triggered biolipid neuroprotectants that along with their associated rescue pathways, contribute to life-or-death decisions of brain cells during homoeostasis, aging and neurodegenerative disease.
我们对阿尔茨海默病（AD）中细胞存活信号的理解取得了重大进展，这源于最近对必需的ω-3脂肪酸二十二碳六烯酸（DHA，C(22:6)，n=3）的代谢、运输和命运的研究。脑突触终末和神经元质膜中DHA高度富集，这种多不饱和脂肪酸的缺乏是AD影响大脑的特征。针对含DHA磷脂的氧化应激以及与年龄相关的DHA耗竭与AD中正常认知功能的逐渐衰退有关。目前的研究支持这样一种观点，即DHA本身以及新型的源自DHA的神经突触和膜衍生脂质信使在体外应激培养的神经细胞模型以及体内学习、记忆和AD的哺乳动物模型中，具有相当大的潜力来调节细胞存活信号。这个内在拯救系统中的关键参与者包括α-分泌酶加工的神经营养因子sAPPα[可溶性APPα（淀粉样前体蛋白α）]肽、源自DHA的10,17S-二十二碳三烯NPD1（神经保护素D1）、生物合成NPD1的串联脑胞质磷脂酶A(2)和15-脂氧合酶酶系统，以及一小类编码Bcl-2、Bcl-X(L)和Bfl-1（A1）的抗凋亡神经保护基因。本文综述了关于DHA和氧化型DHA衍生物NPD1的当前观点，它们是内在触发的生物脂质神经保护剂，与它们相关的拯救途径一起，在体内平衡、衰老和神经退行性疾病期间对脑细胞的生死决策起作用。
