A role for docosahexaenoic acid–derived neuroprotectin D1 in neural cell survival and Alzheimer disease
Walter J. Lukiw, … , Charles N. Serhan, Nicolas G. Bazan
Walter J. Lukiw, … , Charles N. Serhan, Nicolas G. Bazan
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2774-2783. https://doi.org/10.1172/JCI25420.
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Research Article Neuroscience

A role for docosahexaenoic acid–derived neuroprotectin D1 in neural cell survival and Alzheimer disease

Abstract

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-β (Aβ) 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 A2 and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed Aβ42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-α 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 Aβ42-induced neurotoxicity.

Authors

Walter J. Lukiw, Jian-Guo Cui, Victor L. Marcheselli, Merete Bodker, Anja Botkjaer, Katherine Gotlinger, Charles N. Serhan, Nicolas G. Bazan

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Figure 1

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DHA attenuates Aβ peptide secretion and serves as the precursor for NPD1...
DHA attenuates Aβ peptide secretion and serves as the precursor for NPD1 biosynthesis; meanwhile, sAPPα activates NPD1 formation. (A) HN cells were grown for up to 8 weeks. (B and C) After 4 weeks of culture, aging HN cells displayed approximately equal populations of neurons and glia and stained positive with the (red fluorescent) neuron-specific marker βIII tubulin (6) (B) and the (green fluorescent) glia-specific marker GFAP (C). (D and E) HN cells in culture normally release Aβ40 and Aβ42 peptides over 8 weeks of aging. Secretion by HN cells of Aβ42 peptide was approximately one-tenth that of Aβ40 peptide; IL-1β (10 ng/ml in modified HNMM; see ref. 3) increased, and DHA decreased, the release of both Aβ40 and Aβ42 peptides into the cell culture medium. CON, control. (F) DHA (100 nM) induced NPD1 biosynthesis in HN cells, and this induction was age-dependent. (G–I) HN cells incubated in the presence of 10, 20, 50, and 100 ng/ml of sAPPα showed dose-dependent upregulation of NPD1 formation (G); HN cells incubated with sAPPα (at 20 and 100 ng/ml) and/or DHA (at 50 nM; even in the presence of Aβ42) also displayed upregulated production of NPD1 (H and I). *P < 0.05 (ANOVA).