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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Aβ42-induced apoptosis is associated with both neurons and glia. (A) Com...
Aβ42-induced apoptosis is associated with both neurons and glia. (A) Compacted nuclei were associated with both neurons (white arrows) and glia (pink arrows), and with non–βIII tubulin– or non–GFAP-staining cells (non-neural cells; yellow arrows). (B) Apoptosis, as monitored by the presence of compacted nuclei of no more than 0.5 μm diameter (5, 6) after Hoechst 33258 staining, was significantly suppressed by NPD1. Analysis of numbers of compacted nuclei per field in both neurons (red bars) and glia (green bars) shows that these were significantly attenuated in the presence of Aβ42+NPD1 when compared with Aβ42 alone; black bars indicate abundance of compacted nuclei associated with non–βIII tubulin–staining/non–GFAP-staining cells. n = 16. *P < 0.01 and **P < 0.05 versus controls (ANOVA).