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. 2015 Mar;56(3):674–681. doi: 10.1194/jlr.P055418

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

Xiuzhe Wang *,†,1, Erik Hjorth *, Inger Vedin §, Maria Eriksdotter *, Yvonne Freund-Levi *, Lars-Olof Wahlund *, Tommy Cederholm **, Jan Palmblad §, Marianne Schultzberg *
PMCID: PMC4340314  PMID: 25616438

Abstract

Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer’s disease (AD) is associated with brain inflammation 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-β 1–40 showed unchanged levels of the SPMs lipoxin A4 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.

Keywords: amyloid β, Alzheimer’s disease, clinical trials, docosahexaenoic acid, fish oil, inflammation, lipoxin, nutrition, peripheral blood mononuclear cell, resolvin, fatty acid

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.

SUBJECTS AND METHODS

Study design

The OmegAD study enrolled 204 AD patients, with 174 patients completing the trial. This double-blind, placebo-controlled trial randomized the patients to daily oral treatment of n-3 FA-rich supplementation or placebo for 6 months. The patients in the n-3 FA supplementation group received 1.7 g DHA and 0.6 g EPA (EPAX1050TG; Pronova Biocare A/S, Lysaker, Norway) daily, while patients in the placebo group received daily isocaloric placebo oil containing 1 g corn oil, of which 0.6 g linoleic acids were included. All patients received an equal amount of vitamin E supplementation, which was added into the capsules of EPAX1050TG and placebo. The primary outcome of the OmegAD study has been published previously (19).

In total, 17 patients were involved in the present study, and 15 patients concluded the study (2 dropped out), including 8 subjects (mean ± SD of age = 72.5 ± 8.2 years old, 3 females) who received n-3 FA supplementation and 7 subjects (mean ± SD of age = 70.4 ± 6.6 years old, 2 females) who received placebo (29). Peripheral venous blood was collected prior to and after the 6 month treatment, in EDTA-coated tubes. Prior to the treatments, there was no difference between the two groups with regard to age, gender, APOE4, cognitive evaluation by mini-mental state examination test (MMSE), plasma AA, DHA and EPA levels, body weight, and intake of aspirin (supplementary Table 1). There was no change in the cell counts of neutrophils, monocytes, and lymphocytes in the blood after the 6 month treatment (29).

All the patients and their caregivers were informed and gave the written consent before being enrolled in the clinical trial. The studies were approved by the Southern Ethical committee at Karolinska Institutet.

Plasma FA measurements

The levels of plasma FAs before and after the treatment were analyzed by gas chromatography using a TR-Frame column of 30 m length × 0.32 mm diameter × 25 μm film (Thermo Scientific, Waltham, MA). The results were presented as the relative abundance of each FA, as described previously (30).

Plasma transthyretin analysis

Plasma samples of all 174 patients finally included in the OmegAD study have been analyzed previously for transthyretin (TTR) levels (31). Standard nephelometrical assay of TTR using Immage system (Beckman Coulter, Bromma, Sweden) was performed in the Laboratory of Clinical Chemistry, Karolinska University Hospital.

PBMC preparation and ex vivo experiment

PBMCs were isolated from the peripheral venous blood by gradient centrifugation using Lymphoprep solution (Nycomed Pharma, Oslo, Norway). The isolated PBMCs contained an average of 15% monocytes and 85% lymphocytes, before and after treatment, in both treatment groups (29). The cell viability was measured by the trypan blue exclusion assay, and the number of viable cells was ∼96% in both treatment groups (29).

Two millions of isolated PBMCs from each patient were resuspended in 1 ml Hank’s balanced salt solution (Life Technologies, Paisley, Scotland, UK), containing CaCl2 and MgCl2, but without phenol red. The culture medium was supplemented with 0.0149 M HEPES agent (Life Technologies). Penicillin and streptomycin were added into the culture medium to prevent biological contamination. Aβ40 peptide (Bachem, Heidelberg, Germany) was dissolved in DMSO (Sigma, Stockholm, Sweden) and added to the cultures at a final concentration of 7 μM. This concentration was chosen to be in the range of concentrations used in previous studies (32–36). It was shown that 7 µM Aβ40 did not induce significant cell death (33) but could increase the lipid peroxidation (34) that may influence SPM production. A preparation of 7 µM Aβ40, similar to the one used in the present study, results in monomers and dimers in the culture medium (33). The same concentration (1%) of the solvent (DMSO) used for Aβ40, which was present in the cultures treated with Aβ40, was also present in the control (vehicle) cultures. After 22 h incubation at 37°C with 5% CO2, cell cultures were centrifuged, and the supernatants were collected for further analysis of LMs.

Analysis of LMs

Supernatants from the cell cultures were extracted as described previously (13). Briefly, the supernatants were diluted with methanol and water and then acidified to pH 3.5. C18 columns were preconditioned with methanol and then washed with water. The acidified supernatants were immediately applied to the C18 columns at a speed of 0.5 ml/min, after which the columns were washed with water and then hexane. Subsequently, lipids were eluted with methyl formate, which was further evaporated under a nitrogen gas stream. The residue containing lipid contents was resuspended with extraction buffer supplied with the LXA4 enzyme immunoassay (EIA) kit (Oxford Biomedical Research, Oxford, MI).

The extracted lipids were analyzed by EIA assays of the SPMs LXA4 and resolvin D1 (RvD1; Cayman Chemical, Ann Arbor, MI), as well as leukotriene B4 (LTB4; Cayman Chemical). The assays were performed according to the manufacturers’ instructions.

Statistics

All statistical analyses were performed using the SPSS software. Analyses across the two treatment groups were performed by the Mann-Whitney U-test. Wilcoxon signed rank test was applied for analysis of dependent data of paired samples. Correlation analysis was performed with the nonparametric Spearman’s rho test. P < 0.05 was considered as statistically significant.

RESULTS

MMSE

The primary outcome of the OmegAD study with regard to MMSE scores was previously reported (19). The pretrial MMSE score in the n-3 FA supplementation group, included in the present study, was 26.0 ± 2.9 (mean ± SD), while that in the placebo group was 24.4 ± 1.9 (mean ± SD) (P > 0.05 when comparing the two groups). There was a drop by 3.1 (= mean) in MMSE scores in the placebo group after 6 months compared with pretrial scores, whereas there was no change in MMSE scores in the n-3 FA supplement group after 6 months (Fig. 1).

Fig. 1.

Fig. 1.

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MMSE scores before and after the 6 month trial. Paired individual values are flanked by mean ± SD. No statistical significance was found in the n-3 FA supplementation group, but a decrease was found in the placebo group after the 6 month trial.

Plasma FAs

Prior to the oral supplementation of n-3 FAs or placebo, there was no difference between the treatment groups with regard to plasma AA, DHA, or EPA (Fig. 2). After 6 months of treatment, the n-3 FA supplement group had significantly lower levels of AA and higher levels of DHA and EPA compared with the baseline levels before treatment (Fig. 2). The plasma levels of AA decreased 0.5 percentage units, while EPA and DHA levels increased with 2.4 and 3.5 percentage units, respectively.

Fig. 2.

Fig. 2.

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A–C: Levels of plasma AA, DHA, and EPA before and after the 6 month clinical trial. Paired individual values are flanked by mean ± SD. Supplementation of n-3 FAs significantly decreased plasma AA levels (A) and increased DHA (B) and EPA (C) levels in plasma. There were no changes over time in the placebo group.

The ratio between changes in EPA and DHA was 2.4%:3.5% = 0.69:1 in plasma, significantly higher than the EPA:DHA ratio (0.6 g:1.7 g = 0.35:1) in the supplemented preparation (EPAX).

There was no change in AA, DHA, or EPA after the 6 month trial in the placebo group (Fig. 2A–C). In this group, however, there was an outlier patient showing significantly increased levels of plasma DHA and EPA after 6 months (Fig. 2). Analysis of all the results in the present study, with and without data from this patient, resulted in the same statistical significances. Thus, all of the results presented in this study included the outlier.

LMs released by PBMCs

LXA4 and RvD1 levels.

Upon Aβ40 exposure, the release of LXA4 and RvD1 from PBMCs was reduced after 6 months in the placebo supplementation group compared with baseline, while in the n-3 FA supplementation group the levels remained similar to that observed at baseline (Fig. 3A, B).

Fig. 3.

Fig. 3.

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A–D: Levels of LMs in the medium of PBMCs exposed to Aβ40. Paired individual values are flanked by mean ± SD. A, B: Levels of LXA4 and RvD1 were unchanged in the n-3 FA supplementation group, but there was a significant decrease in these two SPMs in the placebo-supplemented group (P < 0.05). C: Levels of LTB4 were unchanged in both patient groups over time. D: The ratio between LXA4 and LTB4 was not changed in the n-3 FA supplementation group, while it was decreased in the placebo group (P < 0.05).

During vehicle (DMSO) conditions, the levels of LXA4 and RvD1 released from PBMCs did not change after 6 months in any one of the two treatment groups (supplementary Fig. 1A, B). There was no statistically significant difference in LXA4 or RvD1 levels between DMSO and Aβ40 conditions (supplementary Fig. 2A, B).

LTB4 levels.

The levels of LTB4 in the supernatant of PBMCs showed no difference after 6 months of treatment with either n-3 FAs or placebo, compared with baseline. This was the case in both cultures of PMBCs treated with Aβ40 (Fig. 3C) or vehicle (supplementary Fig. 1C). The levels of LTB4 were lower upon incubation with Aβ40 as compared with vehicle (DMSO) conditions (supplementary Fig. 2C).

LXA4/LTB4 ratio.

In the supernatant of vehicle-treated cells, the ratio between LXA4 and LTB4 was not altered after 6 months of treatment with n-3 FAs or placebo (supplementary Fig. 1D). When PBMCs were exposed to Aβ40, the LXA4/LTB4 ratio in the placebo group was reduced by 13% (mean) compared with baseline but was similar to the ratio observed at baseline in the n-3 FA treatment group (Fig. 3D). The LXA4/LTB4 ratio was higher upon incubation with Aβ40 compared with that in vehicle (DMSO) conditions (supplementary Fig. 2D).

Correlation analysis

Correlation analysis was performed to relate the change in the levels of SPMs from Aβ40-exposed PBMCs before and after 6 months of treatment with n-3 FA or placebo, with changes in MMSE scores, and plasma FAs and TTR. The data on TTR in all 174 patients have been published previously (31) and showed decreased levels in the placebo group after 6 months, but no significant change in the n-3 FA group. There was no correlation between changes in the levels of SPMs and MMSE scores, neither between plasma levels of AA, DHA, and EPA. A positive correlation (Spearman’s rho test, r = 0.735, P < 0.01) was found between the change in the levels of LXA4 and plasma TTR levels (Fig. 4A). The sum of change in the levels of LXA4 and RvD1 was also correlated to plasma TTR levels, however, to a less extent (Spearman’s rho test, r = 0.556, P < 0.05) (Fig. 4B). No correlation was found between changes in the levels of RvD1 and TTR (Spearman’s rho test, r = −0.021, P = 0.94).

Fig. 4.

Fig. 4.

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A, B: Correlation between changes in release of SPMs from Aβ40-exposed PBMCs and plasma TTR levels. A: LXA4 changes were positively correlated to changes in plasma TTR levels (Spearman’s rho test, r = 0.735, P < 0.01). B: The sum of changes in LXA4 and RvD1 was also correlated to changes in plasma TTR levels (Spearman’s rho test, r = 0.556, P < 0.05).

DISCUSSION

In the present study, we report that treatment of AD patients with an oil rich in DHA had a supportive effect on the production of SPMs by PBMCs ex vivo. Upon Aβ40 exposure, PBMCs from AD patients of the placebo group secreted less LXA4 and RvD1 after 6 months of placebo supplementation, compared with the secretion from PBMCs prior to the trial. These data indicate that the ability to produce SPMs by PBMCs decreases with time, during which the disease progresses. Supplementation with n-3 FAs for 6 months prevented this reduction in SPMs, indicating that a defined n-3 FA supplement can hinder an age- and AD-related deterioration in proresolving signaling.

In an earlier study on patients with AD or mild cognitive impairment, and individuals with subjective cognitive impairment, we found a positive correlation between the levels of SPMs in CSF samples and the MMSE score (13). Taken together with the prevention of age-related deterioration in MMSE scores observed upon n-3 FA supplementation, the present data indicate that a deficiency in the ability to produce proresolving mediators may play a role in the cognitive decline in AD. To explain if this is due to a direct neurotrophic effect, or by removal of harmful proinflammatory activities, further investigation is needed. An anti-inflammatory effect that is present ex vivo after treatment with n-3 FAs was shown in previous studies in the OmegAD trial, where n-3 FA supplementation reduced the levels of proinflammatory cytokines and prostaglandin F2α produced by PBMCs under lipopolysaccharides (LPSs) challenge (29, 37).

Analysis of the levels of LTB4 showed no change, either in the n-3 supplement group or the placebo group. This finding is in line with previous reports in which n-3 FA supplementation did not alter LTB4 release (38, 39); however, it is contrary to other studies, where LTB4 release from PBMCs, or whole blood cells, was reduced by n-3 FA supplementation (40, 41). LTB4 is considered a proinflammatory mediator and may have detrimental effects that are related to AD (42, 43). AA is the precursor for both LXA4 and LTB4, and the ratio between these two LMs produced from AA depends on “class-switching” of enzymes involved in the AA cascade (44). The analysis of this ratio produced results that were along the same line as when analyzing LXA4 alone, showing a decrease in LXA4/LTB4 in Aβ40-exposed PBMCs of the placebo group during the study period, which was prevented by supplementation with n-3 FAs.

Because SPMs are biosynthesized from PUFAs, supplementation of the precursors may theoretically increase the products. A previous study showed that supplementation with n-3 PUFAs rich in DHA and EPA significantly increased the levels of RvD1, RvE1, and protectin D1 (PD1) in adipose tissue from patients with obesity (45). Assuming that changes in plasma FAs can contribute to FA composition in PBMCs, as reported previously in healthy subjects (46), similar changes in SPMs released by PBMCs were envisaged. In the present groups of patients, the relative levels of plasma AA were decreased, and the relative DHA levels were increased, by the n-3 FA supplementation. However, we did not observe any accompanying increase in LXA4 and RvD1 levels released by PBMCs. There were no changes in the relative levels of AA or DHA in the placebo group, but the release of LXA4 and RvD1 from PBMCs was decreased over the 6 months of the study, indicating that without a change in plasma precursor FAs, deterioration in SPM production occurs in AD patients.

Correlation analysis revealed no association between the changes in SPM levels in the culture medium and their precursors in plasma. The OmegAD study was a trial on AD patients, and it has been shown that levels of lipoxygenases (key enzymes involved in SPM biosynthesis) were altered in AD patients (13), thus offering an explanation for the lack of correlation. An implication is therefore that AD patients with an altered capacity to produce SPMs from n-3 FAs may be less sensitive to treatment with the latter. Thus, the levels and functional alterations of lipoxygenases in AD patients need further investigation to understand if and how the ability to produce SPMs is impaired. The trends of changes in SPMs and MMSE scores are similar but lack statistically significant correlation. A possible explanation could be that, unlike in CSF samples, SPM values derived ex vivo from peripheral cells do not reflect the environment in the brain to the same degree. Activities of the immune system have been suggested to be of use as prognostic and diagnostic markers (47), but further investigation is required to determine whether the release of SPMs by PBMCs can be used for this purpose. Moreover, the MMSE scores at baseline revealed that both treatment groups had a modest impairment in cognition, as shown by 26.0 ± 2.9 in the n-3 supplemented group and 24.4 ± 1.9 in the placebo group. Thus, the results presented in this study may not be informative of SPM release from PBMCs obtained from patients with severely affected cognition and a more advanced AD.

A correlation was found between the changes in SPMs secreted by PBMCs and the plasma TTR levels. TTR, originally named prealbumin, was first found to be present in senile plaques (48), and then shown to be able to bind to Aβ and prevent Aβ fibrillization (49). There is ample evidence that TTR counteracts the toxic effects of Aβ in various AD-related models (50–54). LXA4, and its analog aspirin-triggered LXA4, have also been shown to ameliorate the detrimental effects of Aβ in vitro and in vivo (17, 18, 55), probably by increasing phagocytosis, downregulating proinflammatory signaling, and upregulating anti-inflammatory cytokine production (11). RvD1 was also reported to enhance phagocytosis by macrophages (56). Thus, n-3 FA supplementation may favor the capacity of homeostatic functions to handle overabundance of Aβ, as shown by preserved plasma TTR levels, SPM levels released by PBMCs, and an increased phagocytosis of Aβ by microglia upon exposure to DHA and EPA in vitro (57).

In conclusion, our study adds further confirmation to the hypothesis that resolution of inflammation is disturbed in AD patients, as shown by the reduced SPM release from PBMCs over time. Supplementation with n-3 FAs prevented this reduction by a yet unknown mechanism, although the increased availability of precursors presents a plausible explanation. The effects of n-3 FA supplementation on SPM release from PBMCs were associated with plasma TTR levels, a marker in plasma for Aβ clearance, and may have a relation to cognitive status. Whether similar protective effects of n-3 FA supplementation may occur in cells resident in the brain, such as microglia, remains to be further investigated. The n-3 FA supplementation did not increase SPM release from the PBMCs but prevented a reduction in SPM release. A hypothetical impairment, specific for AD, in the enzymatic machinery producing SPMs may blunt the effect of n-3 PUFA treatment and is an important subject of research. Moreover, as the number of subjects in the present study is limited, firm conclusions will need further confirmation in a larger patient population. A therapeutic strategy using SPMs instead of, or together with, their precursors to treat AD may be further considered.

Supplementary Material

Supplemental Data
supp_56_3_674__index.html (1.3KB, html)

Acknowledgments

The authors thank A-C. Tysén-Bäckström and Andreas Svensson for management of patients, and Bengt Vessby and Siv Tengblad for analysis of FAs in the plasma.

Footnotes

Abbreviations:

AA
arachidonic acid
Aβ
amyloid β Aβ40, amyloid-β 1–40
AD
Alzheimer’s disease
CSF
cerebrospinal fluid
LM
lipid mediator
LTB4
leukotriene B4
LXA4
lipoxin A4
MMSE
mini-mental state examination
PBMC
peripheral blood mononuclear cell
RvD1
resolvin D1
SPM
specialized proresolving mediator
TTR
transthyretin

The work was supported by Pronova Biocare A/S, the Swedish Research Council Grants 72VX-14308 and 71X-05991, Chinese Scholarship Council, Stockholm County Council, Swedish Alzheimer Foundation, Gun och Bertil Stohnes Stiftelse, and Stiftelsen för Gamla tjänarinnor. This trial was registered at www.clinicaltrials.gov as #NCT00211159.

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table and two figures.

REFERENCES

  • 1.Griffin W. S., Stanley L. C., Ling C., White L., MacLeod V., Perrot L. J., White C. L., III, Araoz C. 1989. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. USA. 86: 7611–7615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Araujo D. M., Lapchak P. A. 1994. Induction of immune system mediators in the hippocampal formation in Alzheimer’s and Parkinson’s diseases: selective effects on specific interleukins and interleukin receptors. Neuroscience. 61: 745–754. [DOI] [PubMed] [Google Scholar]
  • 3.Rao J. S., Rapoport S. I., Kim H. W. 2011. Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer’s disease brain. Transl. Psychiatry. 1: e31. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 4.Galimberti D., Venturelli E., Fenoglio C., Guidi I., Villa C., Bergamaschini L., Cortini F., Scalabrini D., Baron P., Vergani C., et al. 2008. Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer’s disease and frontotemporal lobar degeneration. J. Neurol. 255: 539–544. [DOI] [PubMed] [Google Scholar]
  • 5.Angelopoulos P., Agouridaki H., Vaiopoulos H., Siskou E., Doutsou K., Costa V., Baloyiannis S. I. 2008. Cytokines in Alzheimer’s disease and vascular dementia. Int. J. Neurosci. 118: 1659–1672. [DOI] [PubMed] [Google Scholar]
  • 6.Bermejo P., Martin-Aragon S., Benedi J., Susin C., Felici E., Gil P., Ribera J. M., Villar A. M. 2008. Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer’s disease. Immunol. Lett. 117: 198–202. [DOI] [PubMed] [Google Scholar]
  • 7.Zuliani G., Cavalieri M., Galvani M., Passaro A., Munari M. R., Bosi C., Zurlo A., Fellin R. 2008. Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J. Neurol. Sci. 272: 164–170. [DOI] [PubMed] [Google Scholar]
  • 8.McGeer P. L., McGeer E. G. 2007. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol. Aging. 28: 639–647. [DOI] [PubMed] [Google Scholar]
  • 9.Trepanier C. H., Milgram N. W. 2010. Neuroinflammation in Alzheimer’s disease: are NSAIDs and selective COX-2 inhibitors the next line of therapy? J. Alzheimers Dis. 21: 1089–1099. [DOI] [PubMed] [Google Scholar]
  • 10.Rangel-Huerta O. D., Aguilera C. M., Mesa M. D., Gil A. 2012. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br. J. Nutr. 107 (Suppl. 2): S159–S170. [DOI] [PubMed] [Google Scholar]
  • 11.Serhan C. N. 2014. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 510: 92–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Lukiw W. J., Cui J. G., Marcheselli V. L., Bodker M., Botkjaer A., Gotlinger K., Serhan C. N., Bazan N. G. 2005. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115: 2774–2783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Wang X., Zhu M., Hjorth E., Cortés-Toro V., Eyjolfsdottir H., Graff C., Nennesmo I., Palmblad J., Eriksdotter M., Sambamurti K., et al. 2015. Resolution of inflammation is altered in Alzheimer’s disease. Alzheimers Dement. 11: 40–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Zhao Y., Calon F., Julien C., Winkler J. W., Petasis N. A., Lukiw W. J., Bazan N. G. 2011. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPAR-γ-mediated mechanisms in Alzheimer’s disease models. PLoS ONE. 6: e15816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Wang X., Puerta E., Cedazo-Minguez A., Hjorth E., Schultzberg M. 2015. Insufficient resolution response in the hippocampus of a senescence-accelerated mouse model - SAMP8. J. Mol. Neurosci. 55: 396–405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zhu M., Wang X., Schultzberg M., Hjorth E. 2015. Differential regulation of resolution in inflammation induced by amyloid-β42 and lipopolysaccharides in human microglia. J. Alzheimers Dis. 43: 1237–1250. [DOI] [PubMed] [Google Scholar]
  • 17.Medeiros R., Kitazawa M., Passos G. F., Baglietto-Vargas D., Cheng D., Cribbs D. H., LaFerla F. M. 2013. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am. J. Pathol. 182: 1780–1789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Dunn H. C., Ager R. R., Baglietto-Vargas D., Cheng D., Kitazawa M., Cribbs D. H., Medeiros R. 2015. Restoration of lipoxin A4 signaling reduces Alzheimer’s disease-like pathology in the 3xTg-AD mouse model. J. Alzheimers Dis. 43: 893–903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Freund-Levi Y., Eriksdotter-Jönhagen M., Cederholm T., Basun H., Faxen-Irving G., Garlind A., Vedin I., Vessby B., Wahlund L. O., Palmblad J. 2006. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63: 1402–1408. [DOI] [PubMed] [Google Scholar]
  • 20.Togo T., Akiyama H., Iseki E., Kondo H., Ikeda K., Kato M., Oda T., Tsuchiya K., Kosaka K. 2002. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol. 124: 83–92. [DOI] [PubMed] [Google Scholar]
  • 21.Malm T. M., Koistinaho M., Parepalo M., Vatanen T., Ooka A., Karlsson S., Koistinaho J. 2005. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18: 134–142. [DOI] [PubMed] [Google Scholar]
  • 22.Stalder A. K., Ermini F., Bondolfi L., Krenger W., Burbach G. J., Deller T., Coomaraswamy J., Staufenbiel M., Landmann R., Jucker M. 2005. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25: 11125–11132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Simard A. R., Soulet D., Gowing G., Julien J. P., Rivest S. 2006. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 49: 489–502. [DOI] [PubMed] [Google Scholar]
  • 24.Grathwohl S. A., Kalin R. E., Bolmont T., Prokop S., Winkelmann G., Kaeser S. A., Odenthal J., Radde R., Eldh T., Gandy S., et al. 2009. Formation and maintenance of Alzheimer’s disease β-amyloid plaques in the absence of microglia. Nat. Neurosci. 12: 1361–1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Michaud J. P., Bellavance M. A., Prefontaine P., Rivest S. 2013. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid β. Cell Reports. 5: 646–653. [DOI] [PubMed] [Google Scholar]
  • 26.Cao C., Are– G. W., Dickson A., Mamcarz M. B., Lin X., Ethell D. W. A. 2009. β-specific Th2 cells provide cognitive and pathological benefits to Alzheimer’s mice without infiltrating the CNS. Neurobiol. Dis. 34: 63–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Gabelle A., Schraen S., Gutierrez L-A., Pays C., Rouaud O., Buée L., Touchon J., Helmer C., Lambert J-C., Berr C. Plasma β-amyloid 40 levels are positively associated with mortality risks in the elderly. Alzheimers Dement. Epub ahead of print. July 8, 2014; 10.1016/j.jalz.2014.04.515. [DOI] [PubMed] [Google Scholar]
  • 28.Speciale L., Calabrese E., Saresella M., Tinelli C., Mariani C., Sanvito L., Longhi R., Ferrante P. 2007. Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol. Aging. 28: 1163–1169. [DOI] [PubMed] [Google Scholar]
  • 29.Vedin I., Cederholm T., Freund Levi Y., Basun H., Garlind A., Faxen Irving G., Eriksdotter Jönhagen M., Vessby B., Wahlund L. O., Palmblad J. 2008. Effects of docosahexaenoic acid-rich omega-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am. J. Clin. Nutr. 87: 1616–1622. [DOI] [PubMed] [Google Scholar]
  • 30.Boberg M., Croon L. B., Gustafsson I. B., Vessby B. 1985. Platelet fatty acid composition in relation to fatty acid composition in plasma and to serum lipoprotein lipids in healthy subjects with special reference to the linoleic acid pathway. Clin. Sci. 68: 581–587. [DOI] [PubMed] [Google Scholar]
  • 31.Faxén-Irving G., Freund-Levi Y., Eriksdotter-Jönhagen M., Basun H., Hjorth E., Palmblad J., Vedin I., Cederholm T., Wahlund L. O. 2013. Effects on transthyretin in plasma and cerebrospinal fluid by DHA-rich n - 3 fatty acid supplementation in patients with Alzheimer’s disease: the OmegAD study. J. Alzheimers Dis. 36: 1–6. [DOI] [PubMed] [Google Scholar]
  • 32.Lorenzo A., Yankner B. A. 1994. β-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA. 91: 12243–12247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Mazur-Kolecka B., Frackowiak J. 2006. Neprilysin protects human neuronal progenitor cells against impaired development caused by amyloid-β peptide. Brain Res. 1124: 10–18. [DOI] [PubMed] [Google Scholar]
  • 34.Mazur-Kolecka B., Golabek A., Nowicki K., Flory M., Frackowiak J. 2006. Amyloid-β impairs development of neuronal progenitor cells by oxidative mechanisms. Neurobiol. Aging. 27: 1181–1192. [DOI] [PubMed] [Google Scholar]
  • 35.Lam F. C., Liu R., Lu P., Shapiro A. B., Renoir J. M., Sharom F. J., Reiner P. B. 2001. β-Amyloid efflux mediated by p-glycoprotein. J. Neurochem. 76: 1121–1128. [DOI] [PubMed] [Google Scholar]
  • 36.Tew D. J., Bottomley S. P., Smith D. P., Ciccotosto G. D., Babon J., Hinds M. G., Masters C. L., Cappai R., Barnham K. J. 2008. Stabilization of neurotoxic soluble β-sheet-rich conformations of the Alzheimer’s disease amyloid-β peptide. Biophys. J. 94: 2752–2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Vedin I., Cederholm T., Freund-Levi Y., Basun H., Hjorth E., Faxén Irving G., Eriksdotter-Jönhagen M., Schultzberg M., Wahlund L. O., Palmblad J. 2010. Reduced prostaglandin F2{alpha} release from blood mononuclear leukocytes after oral supplementation of {omega}3 fatty acids: the OmegAD study. J. Lipid Res. 51: 1179–1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Cipollina C., Salvatore S. R., Muldoon M. F., Freeman B. A., Schopfer F. J. 2014. Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. PLoS ONE. 9: e94836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Mølvig J., Pociot F., Worsaae H., Wogensen L. D., Baek L., Christensen P., Mandrup-Poulsen T., Andersen K., Madsen P., Dyerberg J., et al. 1991. Dietary supplementation with omega-3-polyunsaturated fatty acids decreases mononuclear cell proliferation and interleukin-1β content but not monokine secretion in healthy and insulin-dependent diabetic individuals. Scand. J. Immunol. 34: 399–410. [DOI] [PubMed] [Google Scholar]
  • 40.Schubert R., Kitz R., Beermann C., Rose M. A., Baer P. C., Zielen S., Boehles H. 2007. Influence of low-dose polyunsaturated fatty acids supplementation on the inflammatory response of healthy adults. Nutrition. 23: 724–730. [DOI] [PubMed] [Google Scholar]
  • 41.Kelley D. S., Taylor P. C., Nelson G. J., Schmidt P. C., Ferretti A., Erickson K. L., Yu R., Chandra R. K., Mackey B. E. 1999. Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. Lipids. 34: 317–324. [DOI] [PubMed] [Google Scholar]
  • 42.Amtul Z., Uhrig M., Wang L., Rozmahel R. F., Beyreuther K. 2012. Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer’s disease: structural insight. Neurobiol. Aging. 33: 831.e21–831.e31. [DOI] [PubMed] [Google Scholar]
  • 43.Joshi Y. B., Di Meco A., Pratico D. 2014. Modulation of amyloid-β production by leukotriene B4 via the γ-secretase pathway. J. Alzheimers Dis. 38: 503–506. [DOI] [PubMed] [Google Scholar]
  • 44.Levy B. D., Clish C. B., Schmidt B., Gronert K., Serhan C. N. 2001. Lipid mediator class switching during acute inflammation: signals in resolution. Nat. Immunol. 2: 612–619. [DOI] [PubMed] [Google Scholar]
  • 45.Itariu B. K., Zeyda M., Hochbrugger E. E., Neuhofer A., Prager G., Schindler K., Bohdjalian A., Mascher D., Vangala S., Schranz M., et al. 2012. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am. J. Clin. Nutr. 96: 1137–1149. [DOI] [PubMed] [Google Scholar]
  • 46.Yaqoob P., Pala H. S., Cortina-Borja M., Newsholme E. A., Calder P. C. 2000. Encapsulated fish oil enriched in α-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions. Eur. J. Clin. Invest. 30: 260–274. [DOI] [PubMed] [Google Scholar]
  • 47.Tan Z. S., Beiser A. S., Vasan R. S., Roubenoff R., Dinarello C. A., Harris T. B., Benjamin E. J., Au R., Kiel D. P., Wolf P. A., et al. 2007. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology. 68: 1902–1908. [DOI] [PubMed] [Google Scholar]
  • 48.Shirahama T., Skinner M., Westermark P., Rubinow A., Cohen A. S., Brun A., Kemper T. L. 1982. Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaque, in the neurofibrillary tangle, and in the microangiopathic lesion. Am. J. Pathol. 107: 41–50. [PMC free article] [PubMed] [Google Scholar]
  • 49.Schwarzman A. L., Gregori L., Vitek M. P., Lyubski S., Strittmatter W. J., Enghilde J. J., Bhasin R., Silverman J., Weisgraber K. H., Coyle P. K., et al. 1994. Transthyretin sequesters amyloid β protein and prevents amyloid formation. Proc. Natl. Acad. Sci. USA. 91: 8368–8372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Stein T. D., Johnson J. A. 2002. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J. Neurosci. 22: 7380–7388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Carro E., Trejo J. L., Gomez-Isla T., LeRoith D., Torres-Aleman I. 2002. Serum insulin-like growth factor I regulates brain amyloid-β levels. Nat. Med. 8: 1390–1397. [DOI] [PubMed] [Google Scholar]
  • 52.Choi S. H., Leight S. N., Lee V. M., Li T., Wong P. C., Johnson J. A., Saraiva M. J., Sisodia S. S. 2007. Accelerated Aβ deposition in APPswe/PS1δE9 mice with hemizygous deletions of TTR (transthyretin). J. Neurosci. 27: 7006–7010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Buxbaum J. N., Ye Z., Reixach N., Friske L., Levy C., Das P., Golde T., Masliah E., Roberts A. R., Bartfai T. 2008. Transthyretin protects Alzheimer’s mice from the behavioral and biochemical effects of Aβ toxicity. Proc. Natl. Acad. Sci. USA. 105: 2681–2686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Costa R., Ferreira-da-Silva F., Saraiva M. J., Cardoso I. 2008. Transthyretin protects against Aβ peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor. PLoS ONE. 3: e2899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Wu J., Wang A., Min Z., Xiong Y., Yan Q., Zhang J., Xu J., Zhang S. 2011. Lipoxin A4 inhibits the production of proinflammatory cytokines induced by β-amyloid in vitro and in vivo. Biochem. Biophys. Res. Commun. 408: 382–387. [DOI] [PubMed] [Google Scholar]
  • 56.Mizwicki M. T., Liu G., Fiala M., Magpantay L., Sayre J., Siani A., Mahanian M., Weitzman R., Hayden E., Rosenthal M. J., et al. 2013. 1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer’s disease patients. J. Alzheimers Dis. 34: 155–170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Hjorth E., Zhu M., Toro V. C., Vedin I., Palmblad J., Cederholm T., Freund-Levi Y., Faxen-Irving G., Wahlund L. O., Basun H., et al. 2013. Omega-3 fatty acids enhance phagocytosis of Alzheimer’s disease-related amyloid- β42 by human microglia and decrease inflammatory markers. J. Alzheimers Dis. 35: 697–713. [DOI] [PubMed] [Google Scholar]

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