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

Many diseases of the brain display signs of inflammation, including Alzheimer’s disease (AD), the most common type of dementia. The association between inflammation and AD is evidenced from many different disciplines of research. Postmortem studies have revealed increased levels of proinflammatory 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 proinflammatory markers in cerebrospinal fluid (CSF) (4) and plasma/serum (5–7) samples. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory 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 beneficial effects in the regulation of inflammation (10). PUFAs can modulate the inflammatory response by changing cell membrane fluidity 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 inflammation 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/healing. It is, therefore, likely that many of the beneficial effects of PUFAs are dependent on the formation of SPMs. The known SPMs include arachidonic acid (AA)-derived lipoxins, the DHA-derived resolvin D series, neuroprotectins, maresins, and the EPA-derived resolvin E (RvE) series (11). Upon binding to their specific receptors, SPMs downregulate proinflammatory signals and promote the healing process of the tissue (11). Recent studies have indicated that resolution of inflammation is disturbed in AD (12, 13) and AD-related models (14–16). Treatment with one of the SPMs, lipoxin A4 (LXA4), has been demonstrated to rescue synaptic loss and reduce AD-like pathologies in transgenic AD mouse models (17, 18). These studies suggest that stimulating resolution of inflam­mation with SPMs is a promising new strategy for AD therapy. The OmegAD study, the first prospective large randomized clinical trial using DHA and EPA to treat AD patients, showed that supplementation with these PUFAs could reduce the rate of cognitive decline in very mild AD cases (19). The mechanism of this effect is unknown but may be due to beneficial modulation of inflammation, and therefore, resolution is implicated. Although it is technically difficult to directly investigate the function of microglia, the resident cells with immune function in the brain in live patients, peripheral blood mononuclear cells (PBMCs), represent a useful model to assess the effect of treatments on general aspects of immune function. PBMCs, such as T lymphocytes and monocytes, can in certain circumstances infiltrate into the AD brain, or move along brain vessel walls, and directly participate in the inflammation process (20–25). Moreover, PBMCs can influence amyloid-β (Aβ) metabolism without infiltration into the CNS (26). Aβ is the main component of the senile plaques that characterize the brain afflicted by AD and is produced from amyloid precursor protein through the activity of β- and γ-secretase. Of the various lengths produced, amyloid-β 1–40 (Aβ40) and amyloid-β 1–42 (Aβ42) are the most common forms. Aβ40 levels in plasma are higher than those of Aβ42 (27). Interestingly, Aβ40 was shown to decrease the production of the anti-inflammatory cytokine interleukin (IL)-10 by PBMCs from AD patients (28). IL-10 has been shown to be decreased in the hippocampus of AD patients (13). Thus, the effect of Aβ40 on PBMCs indicates its ability to impair anti-inflammatory signaling in a way that is relevant to AD, in addition to its well-known proinflammatory properties. In the present study, we aimed to investigate whether oral treatment with DHA and EPA in AD patients for 6 months affects the production of SPMs by Aβ40-exposed PBMCs, and whether there is a link to the treatment effects on cognition and other related biomarkers.