Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study

Abstract

This article is available online at http://www.jlr.org Many diseases of the brain display signs of infl ammation, including Alzheimer's disease (AD), the most common type of dementia. The association between infl ammation and AD is evidenced from many different disciplines of research. Postmortem studies have revealed increased levels of proinfl ammatory cytokines in the AD brain ( 1-3 ), particularly around the amyloid plaques, and further support is provided by analysis of clinical samples from AD patients, including elevated proinfl ammatory markers in cerebrospinal fl uid (CSF) ( 4 ) and plasma/serum ( 5-7 ) samples. Epidemiological studies have shown that longterm use of nonsteroidal anti-infl ammatory drugs (NSAIDs) confers reduced prevalence of AD ( 8 ). However, prospective clinical trials based on NSAIDs have not been successful in reducing the cognitive decline in AD ( 8, 9 ).Consumption of PUFAs, especially the n-3 FAs DHA and EPA, is well known for benefi cial effects in the regulation of infl ammation ( 10 ). PUFAs can modulate the infl ammatory response by changing cell membrane fl uidity and composition, leading to effects on the function of receptors, and the conductance of ion channels involved in immune activation. In recent years, the concept of resolution of infl ammation has received attention due to the discovery of specialized proresolving mediators (SPMs). SPMs are lipid mediators (LMs) derived from PUFAs and play a key role in resolution, in which the tissue is restored by removal of cellular and molecular debris, and regeneration/ Abstract Specialized proresolving mediators (SPMs) induce resolution of infl ammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their benefi cial effects. It is unknown whether supplementation with PUFAs infl uences the production of SPMs. Alzheimer's disease (AD) is associated with brain infl ammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-␤ 1-40 showed unchanged levels of the SPMs lipoxin A 4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis

“…This resolution pathway is also found to be dysfunctional in Alzheimer disease (72,73). Moreover, -3 supplementation or RvD1 prevents cognitive decline in animal models (74), improves amyloid-␤ phagocytosis, and regulates inflammation in Alzheimer patients (75)(76)(77).…”

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…It has been well established that oral supplementation with omega-3 fatty acids or diets rich in their marine sources increase both plasma and cell-membrane levels of EPA and DHA (Grenon, Owens et al 2015, Wang, Hjorth et al 2015). Unfortunately, the relationship between blood levels of these n-3 fatty acids and the downstream biochemical pathways producing SPM is poorly understood.…”

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

“…Very recently, it was shown that upon Aβ40 exposure, peripheral blood mononuclear cells from AD patients secreted less LXA4 and RvD1 together with the disease progression. Importantly, dietary supplementation of DHA prevented this reduction (Wang et al, 2015a), suggesting that LC n-3 PUFA protect from the AD-associated inflammation through the promotion of pro-resolving signalling pathways. Interestingly, LOX and LTB4 expression increases while LXA4 decreases in the brain of aged and AD mice models (Dunn et al, 2015).…”