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 2

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Aβ42-induced apoptosis is inhibited by NPD1 in HN cells. After 3 weeks i...
Aβ42-induced apoptosis is inhibited by NPD1 in HN cells. After 3 weeks in culture, HN cells were treated with DMEM/F12 (control), Aβ42 (8 μM) in DMEM/F12 (Aβ42), or Aβ42 (8 μM) plus NPD1 (50 nM) (Aβ42+NPD1) in DMEM/F12 for 3.5 days, then stained with Hoechst 33258 (Hoechst), anti–βIII tubulin (βIII tubulin), and anti-GFAP (GFAP), and all 3 stains were imaged together (merge A). As revealed by Hoechst staining, in controls, relatively few compact nuclei were observed; in Aβ42-treated cells, many compact nuclei were seen (white arrows). In Aβ42-treated cells, neurons and glia clumped together with condensed cytoplasm and damaged nuclei, and both βIII tubulin and GFAP staining was reduced (compare merges of control, Aβ42, and Aβ42+NPD1-treated cells). When NPD1 was added to Aβ42-treated cells, Hoechst staining revealed many fewer compacted nuclei. Each field under columns marked βIII tubulin, GFAP, and merge A represents approximately 0.1 mm2. A comparison of control, Aβ42-treated, and Aβ42+NPD1-treated HN cells at higher magnification, stained with Hoechst 33258 (blue), anti–βIII tubulin (red), and anti-GFAP (green), shows that Aβ42-induced apoptosis is associated with both neuronal and glial nuclei (merge B), and that Aβ42+NPD1-treated HN cells show significantly decreased numbers of compacted apoptotic nuclei (yellow arrows).