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.

A neuroscientist's guide to lipidomics

“…Docosahexaenoic acid oxygenation is thought to proceed through two main pathways: a lipoxygenase-mediated pathway, which converts docosahexaenoic acid to resolvins and neuroprotectins (such as neuroprotectin D1 (ref. 94)), two families of lipid signals with marked anti-inflammatory and neuroprotective effects [95][96][97] ; and a free-radical-mediated peroxidation pathway that leads to the production of neuroprostanes, which are involved in oxidative stress 98 . Both mechanisms may be relevant to the alterations in docosahexaenoic acid levels observed in aging and Alzheimer's disease [95][96][97][99][100][101][102] .…”

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

“…Although we did not detect reduced inflammatory cytokines in DHA fed AD model mice, the arachidonic acid levels were significantly reduced, suggesting potential NSAID-like activity of dietary omega-3 to reduce pro-inflammatory prostaglandin intermediates. Other AD-relevant DHA actions may include effects on metabolism to form neuroprotectin D1, an anti-apoptotic DHA metabolite that is dramatically reduced in AD [21].…”

Docosanoids are multifunctional regulators of neural cell integrity and fate: Significance in aging and disease

“…IL-1β stimulates gamma-secretase-mediated cleavage of βAPP into Aβ peptides. Conversely, DHA suppresses both Aβ40 and Aβ42 peptide release with concomitant NPD1 synthesis [25]. Moreover, NPD1 inhibits Aβ42-induced apoptosis in HN cells.…”

“…This suggests that although Aβ42 is activating cell-damaging signals, and yet it is unable to overwhelm endogenous survival signaling. Also, there was an early onset of apoptosis and changes in gene-expression patterns that resemble neurodegenerative events characteristic of AD [25]. Accumulation of secreted Aβ40 and Aβ42 peptides during HN cell aging has implications in the development of Aβ-related neuropathology.…”

“…In fact, NPD1 also induces the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in oxidatively challenged human RPE cells and promotes cytoprotection [8,10]. A further suggestion of the significance of NPD1 in AD is the finding that hippocampal CA1 from AD patients shows a major reduction in NPD1 [25]. Thus, the interplay of DHAderived neuroprotective signaling aims to counteract proinflammatory, cell-damaging events triggered by multiple, converging cytokine and amyloid peptide factors in AD.…”