A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease.
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.
Lukiw
Walter J
WJ
Louisiana State University Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, Louisiana 70112, USA. wlukiw@lsuhsc.edu
Cui
Jian-Guo
JG
Marcheselli
Victor L
VL
Bodker
Merete
M
Botkjaer
Anja
A
Gotlinger
Katherine
K
Serhan
Charles N
CN
Bazan
Nicolas G
NG
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments / Q000633:toxicity; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C075222:amyloid beta-protein (1-42); D051020:bcl-X Protein; C487679:protectin D1; D004281:Docosahexaenoic Acids; D001093:Arachidonate 15-Lipoxygenase; D010741:Phospholipases A; D054467:Phospholipases A2