A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease
A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease
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DOI：
10.1172/jci25420
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Bazan, NG
中科院分区：
文献类型：
--
作者：
Lukiw, WJ;Cui, JG;Bazan, NG
二十二碳六烯酸（DHA）是一种对大脑至关重要的ω - 3脂肪酸，其缺乏与认知能力下降有关。在此我们报道，在细胞因子应激的人类神经细胞中，DHA可减少淀粉样蛋白β（Aβ）的分泌，同时伴有NPD1的形成，NPD1是一种新的由DHA衍生的10,17S - 二十二碳三烯。在阿尔茨海默病（AD）的海马CA1区，DHA和NPD1减少，但在同一大脑的丘脑或枕叶中没有减少。在AD海马中，NPD1生物合成的关键酶——胞质磷脂酶A₂和15 - 脂氧合酶的表达发生了改变。NPD1抑制Aβ42触发的促炎基因的激活，同时上调编码Bcl - 2、Bcl - xl和Bfl - 1（A1）的抗凋亡基因。可溶性淀粉样前体蛋白 - α刺激由DHA合成NPD1。这些结果表明，NPD1通过诱导抗凋亡和神经保护基因表达程序来促进脑细胞存活，从而抑制Aβ42诱导的神经毒性。
Deficiency in docosahexaenoic acid (DHA), a brain-essential omega-3 fatty acid, is associated with cognitive decline. Here we report that,,in cytokine-stressed human neural cells, DHA attenuates amyloid-P (AP) secretion, an effect accompanied by the formation of NPD1, a novel, DHA-derived 10,17S-docosatriene. DHA and NPD1 were reduced in Alzheimer disease (AD) hippocampal cornu ammonis region 1, but not in the thalamus or occipital lobes from the same brains. The expression of key enzymes in NPD1 biosynthesis, cytosolic phospholipase A(2) and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed A beta 42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-a stimulated NPD1 biosynthesis from DHA. These results indicate that NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress A beta 42-induced neurotoxicity.