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 4

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Changes in gene expression in HN cells in the presence of Aβ42 (A), DHA ...
Changes in gene expression in HN cells in the presence of Aβ42 (A), DHA (B), and NPD1 (C). Truncated volcano plots display gene-expression patterns as a function of fold change over age-matched controls, against P (ANOVA). “Nonsignificant genes” that would normally appear in the region of P < 0.05 and fold change of less than 1.0 (either up- or downregulated) have been omitted for clarity. Genes of highest statistical significance are sequestered into the lower left (blue, downregulated) and lower right (red, upregulated) quadrants; further data for a select group of 10 highly significant up- and downregulated genes appear in Table 1 and in Supplemental Table 1. (D) Western immunoblot analysis confirmed upregulation of Bcl-2 and Bfl-1(A1) antiapoptotic proteins over actin controls in DHA- and NPD1-treated cells. Gene transcripts have been classified according to their known major functions, although most of these RNAs may have multiple cellular functions (33). (E) Quantified intensities of Bcl-2 and Bfl-1(A1) bands normalized to constitutively expressed actin in the same sample are shown as bar graphs. *P < 0.02 versus controls.