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-beta (Abeta) 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 Abeta42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-alpha 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 Abeta42-induced neurotoxicity.

• Authors: Walter J Lukiw, Jian-Guo Cui, Victor L Marcheselli, Merete Bodker, Anja Botkjaer, Katherine Gotlinger, Charles N Serhan, Nicolas G Bazan
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 10 Pg. 2774-83 (Oct 2005) ISSN: 0021-9738 [Print] United States
• PMID: 16151530 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• BCL2-related protein A1
• BCL2L1 protein, human
• Minor Histocompatibility Antigens
• Peptide Fragments
• Proto-Oncogene Proteins c-bcl-2
• amyloid beta-protein (1-42)
• bcl-X Protein
• protectin D1
• Docosahexaenoic Acids
• Arachidonate 15-Lipoxygenase
• Phospholipases A
• Phospholipases A2

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (metabolism, toxicity)
• Apoptosis (drug effects)
• Arachidonate 15-Lipoxygenase (genetics, metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Docosahexaenoic Acids (metabolism)
• Enzyme Activation (drug effects)
• Hippocampus (metabolism, pathology)
• Humans
• Minor Histocompatibility Antigens
• Peptide Fragments (toxicity)
• Phospholipases A (metabolism)
• Phospholipases A2
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Thalamus (metabolism, pathology)
• Up-Regulation (drug effects)
• bcl-X Protein (genetics, metabolism)