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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NPD1 and DHA are reduced in AD brain. (A) When compared with age-matched...
NPD1 and DHA are reduced in AD brain. (A) When compared with age-matched controls, NPD1 and unesterified DHA were significantly reduced in AD hippocampus (HIP) and temporal lobe (TEM) but not in the thalamus (THA) or occipital lobe (OCC) of the same AD brains. In AD, thalamic and occipital regions were relatively spared AD neuropathology. Signals for NPD1 and unesterified DHA in AD hippocampus averaged about one-twentieth and one-half, respectively, of those values seen in age-matched controls. LC-PDA-ESI-MS-MS–based lipidomic analysis (sensitivity 0.05 pmol/mg total protein). n = 6. *P < 0.01 (ANOVA). (B) Characterization of NPD1 using LC-PDA-ESI-MS-MS–based lipidomic analysis (5, 6). (C) Mass spectrographic identification of 10,17S-docosatriene (NPD1) in human hippocampus. (D) Proposed biosynthetic pathways from DHA to NPD1 and bioactivity. DHA is highly enriched as an acyl side chain of brain and retinal membrane phospholipids, suggesting its importance as an essential component of brain and retinal function (2, 29). Esterified DHA is liberated by PLA2 action upon membrane phospholipids, whereupon it is oxygenated, initially via a 15-LOX–like enzyme, into 10,17S-docosatriene (NPD1). sAPPα, a secreted neurotrophic peptide, stimulates NPD1 biosynthesis. NPD1 exhibits neuroprotective activity against Aβ42 action, represses apoptosis, and promotes the expression of antiapoptotic genes encoding Bcl-2 and Bfl-1(A1) (37).