Cerebrospinal Fluid Profile of Lipid Mediators in Alzheimer's Disease.

Alzheimer's disease (AD) develops into dementia over a period of several years, during which subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) can be used as intermediary diagnoses of increasing severity. Chronic neuroinflammation resulting from insufficient resolution is involved in the pathogenesis of AD and is associated with cognitive impairment. Specialized pro-resolving lipid mediators (LMs) that promote the resolution of inflammation may be valuable markers in AD diagnosis and as therapeutic targets. Liquid chromatography-tandem mass spectrometry was used to analyze pro-resolving and pro-inflammatory LMs in cerebrospinal fluid (CSF) from patients with cognitive impairment ranging from subjective impairment to a diagnosis of AD and correlated to cognition, CSF tau, and ß-amyloid. Resolvin (Rv) D4, RvD1, neuroprotectin D1 (NPD1), maresin 1 (MaR1), and RvE4 were lower in AD and/or MCI compared to SCI. The pro-inflammatory LTB4 and 15-HETE were higher in AD and MCI, respectively, while PGD2, PGE2, and PGF2a were decreased in AD, compared to SCI. RvD4 was also negatively correlated to AD tangle biomarkers, and positive correlations to cognitive test scores were observed for both pro-resolving LMs and their precursor fatty acids. In this exploratory study of the lipidome in CSF of AD, MCI, and SCI, the results indicate a shift in the LM profile from pro-resolving to pro-inflammatory in progression to AD, suggesting that it may be of use as a biomarker when followed by confirmation by replication studies.

Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice.

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer's disease (AD). Resolution of inflammation follows neutralization of pathogens and is a response to limit damage and promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution is impaired in AD brains, we decided to test if intranasal administration of pro-resolving LMs in the AppNL-G-F/NL-G-F mouse model for AD could resolve inflammation and ameliorate pathology in the brain. A mixture of the pro-resolving LMs resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) and neuroprotectin D1 (NPD1) was administered to stimulate their respective receptors. We examined amyloid load, cognition, neuronal network oscillations, glial activation and inflammatory factors. The treatment ameliorated memory deficits accompanied by a restoration of gamma oscillation deficits, together with a dramatic decrease in microglial activation. These findings open potential avenues for therapeutic exploration of pro-resolving LMs in AD, using a non-invasive route.

Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study.

BACKGROUND: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. OBJECTIVE: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). METHODS: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aß 38, Aß 40, Aß 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. RESULTS: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. CONCLUSION: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease.

Sustained brain chronic inflammation in Alzheimer's disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates ß-amyloid (Aß) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aß pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.

Cerebrospinal Fluid Inflammatory Markers in Alzheimer's Disease: Influence of Comorbidities.

BACKGROUND: Alzheimer's disease (AD) develops into dementia after several years, and subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are used as intermediary diagnoses of increasing severity. Inflammation is an important part of AD pathology and provides potential novel biomarkers and treatment targets. OBJECTIVE: To identify novel potential biomarkers of AD in cerebrospinal fluid (CSF) and create a molecular pattern of inflammatory factors providing differentiation between AD and SCI. METHODS: We analyzed 43 inflammatory-related mediators in CSF samples from a cohort of SCI and AD cases vetted for confounding factors (Training cohort). Using multivariate analysis (MVA), a model for discrimination between SCI and AD was produced, which we then applied to a larger nonvetted cohort (named Test cohort). The data were analyzed for factors showing differences between diagnostic groups and factors that differed between the vetted and non-vetted cohorts. The relationship of the factors to the agreement between model and clinical diagnosis was investigated. RESULTS: A good MVA model able to discriminate AD from SCI without including tangle and plaque biomarkers was produced from the Training cohort. The model showed 50% agreement with clinical diagnosis in the Test cohort. Comparison of the cohorts indicated different patterns of factors distinguishing SCI from AD. As an example, soluble interleukin (IL)-6Rα showed lower levels in AD cases in the Training cohort, whereas placental growth factor (PlGF) and serum amyloid A (SAA) levels were higher in AD cases of the Test cohort. The levels of p-tau were also higher in the Training cohort. CONCLUSION: This study provides new knowledge regarding the involvement of inflammation in AD by indicating different patterns of factors in CSF depending on whether potential confounding comorbidities are present or not, and presents sIL-6Rα as a potential new biomarker for improved diagnosis of AD.

Maresin 1 attenuates pro-inflammatory activation induced by ß-amyloid and stimulates its uptake.

Alzheimer's disease (AD) is the most common dementia, characterized by pathological accumulation of ß-amyloid (Aß) and hyperphosphorylation of tau protein, together with a damaging chronic inflammation. The lack of effective treatments urgently warrants new therapeutic strategies. Resolution of inflammation, associated with beneficial and regenerative activities, is mediated by specialized pro-resolving lipid mediators (SPMs) including maresin 1 (MaR1). Decreased levels of MaR1 have been observed in AD brains. However, the pro-resolving role of MaR1 in AD has not been fully investigated. In the present study, human monocyte-derived microglia (MdM) and a differentiated human monocyte cell line (THP-1 cells) exposed to Aß were used as models of AD neuroinflammation. We have studied the potential of MaR1 to inhibit pro-inflammatory activation of Aß and assessed its ability to stimulate phagocytosis of Aß42 . MaR1 inhibited the Aß42 -induced increase in cytokine secretion and stimulated the uptake of Aß42 in both MdM and differentiated THP-1 cells. MaR1 was also found to decrease chemokine secretion and reduce the associated increase in the activation marker CD40. Activation of kinases involved in transduction of inflammation was not affected by MaR1, but the activity of nuclear factor (NF)-κB was decreased. Our data show that MaR1 exerts effects that indicate a pro-resolving role in the context of AD and thus presents itself as a potential therapeutic target for AD.

Receptors for pro-resolving mediators are increased in Alzheimer's disease brain.

Neuroinflammation is a key element of AD pathology and conceivably a result of a disturbed resolution. Resolution of inflammation is an active process which is strictly orchestrated following the acute inflammatory response after removal of the inflammatory stimuli. Acute inflammation is actively terminated by specialized pro-resolving mediators (SPMs) thereby promoting healing and return to homeostasis. Failed resolution may contribute to persistent neuroinflammation and aggravate AD pathology. BLT1 (leukotriene B4 receptor) and ChemR23 (chemerin receptor 23) are receptors for the SPM resolvin (Rv) E1 and are important clinical targets for ending inflammation. In AD, the levels of SPMs are decreased, and pro-inflammatory mediators are increased. In the current study, the distribution of BLT1 and ChemR23 receptors in control brains and in AD as well as correlations with AD pathology was examined for the first time. BLT1 and ChemR23 were analyzed in different regions of post-mortem human brain from cases with AD, early-onset AD and mild cognitive impairment (MCI) and healthy controls, using western blotting and immunohistochemistry. BLT1 and ChemR23 were detected in neurons and glial cells in all examined regions of the human brain, with markedly higher levels in AD than in controls. The receptor levels correlated with the density of staining for the inflammation markers HLA-DR and YKL-40 for microglia and astrocytes, respectively, and elevated staining coincided with high Braak stages in AD. The relative staining densities of these receptors were higher in the basal forebrain, cingulate gyrus and hippocampal regions compared to the cerebellum and frontal cortex (BA46). In conclusion, alterations in the expression of the resolution receptor BLT1 in AD have not been reported previously and the changes in both BLT1 and ChemR23 suggest a disturbed resolution pathway in several regions of the AD brain that may play a role in disease pathology.

RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome.

Inflammation can be resolved by pro-homeostatic lipids called specialized pro-resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle-aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro-inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age-matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.

Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease: The OmegAD Study.

BACKGROUND: Trials of supplementation with omega-3 fatty acids (ω3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω3-FAs in relation to brain atrophy and cognitive decline. OBJECTIVE: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of ω3-FAs supplementation on cognitive performance in moderate AD. METHODS: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE≥15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA. RESULTS: We found significant interactions between ω3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7µmol/L, ω3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo. CONCLUSION: The effect of ω3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of ω3-FA on cognition.

Amyloid-ß Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity.

A new generation of ligands designed to interact with the α-helix/ß-strand discordant region of the amyloid-ß peptide (Aß) and to counteract its oligomerization is presented. These ligands are designed to interact with and stabilize the Aß central helix (residues 13-26) in an α-helical conformation with increased interaction by combining properties of several first-generation ligands. The new peptide-like ligands aim at extended hydrophobic and polar contacts across the central part of the Aß, that is, "clamping" the target. Molecular dynamics (MD) simulations of the stability of the Aß central helix in the presence of a set of second-generation ligands were performed and revealed further stabilization of the Aß α-helical conformation, with larger number of polar and nonpolar contacts between ligand and Aß, compared to first-generation ligands. The synthesis of selected novel Aß-targeting ligands was performed in solution via an active ester coupling approach or on solid-phase using an Fmoc chemistry protocol. This included incorporation of aliphatic hydrocarbon moieties, a branched triamino acid with an aliphatic hydrocarbon tail, and an amino acid with a 4'- N, N-dimethylamino-1,8-naphthalimido group in the side chain. The ability of the ligands to reduce Aß1-42 neurotoxicity was evaluated by gamma oscillation experiments in hippocampal slice preparations. The "clamping" second-generation ligands were found to be effective antineurotoxicity agents and strongly prevented the degradation of gamma oscillations by physiological concentration of monomeric Aß1-42 at a stoichiometric ratio.

Can inflammation be resolved in Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and dementia. Accumulating evidence suggests that inflammation is involved in the pathogenesis of AD. Epidemiological studies suggest that use of anti-inflammatory drugs is associated with a lower incidence of AD. However, clinical trials with anti-inflammatory drugs have not been successful. Recent studies have shown that inflammation is resolved by a process that is mediated by a group of lipid mediators, so called specialized pro-resolving lipid mediators (SPMs). Unlike anti-inflammatory strategies, which usually involve inhibition of the synthesis of inflammatory mediators, stimulating the resolution of inflammation is aimed at ending inflammation in a similar fashion as under normal physiological conditions. We have previously shown that pathways of resolution are impaired in AD. Moreover, we found that SPMs can improve neuronal survival and increase microglial phagocytosis of amyloid beta (Aß) in in vitro studies, indicating that stimulating resolution of inflammation may be a potential therapeutic target in AD. In this review, we summarize recent findings regarding resolution of inflammation in AD. We also discuss possible strategies to stimulate the resolution of inflammation in AD, specifically focusing on signaling pathways, including SPMs, their receptors and enzymes involved in their formation.

Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

Synthesis and in Vitro Evaluation of Monodisperse Amino-Functional Polyester Dendrimers with Rapid Degradability and Antibacterial Properties.

Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride-promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties.

DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study.

Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aß42 Phagocytosis.

Inflammation in the brain is a prominent feature in Alzheimer's disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study, we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1), and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated ß-amyloid (Aß)42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aß42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.

Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study.

BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known. OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.

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

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-ß 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.

Differential regulation of resolution in inflammation induced by amyloid-ß42 and lipopolysaccharides in human microglia.

Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-ß (Aß) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of the resolution cascade. In this pursuit, we exposed microglia to Aß42, and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (α7nAChR) and peroxisome proliferator-activated receptor (PPAR)-δ whereas Aß42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Aß42. Further studies may prove if Aß42-induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD.

Resolution of inflammation is altered in Alzheimer's disease.

BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.

Insufficient resolution response in the hippocampus of a senescence-accelerated mouse model--SAMP8.

Aging is the primary risk factor for Alzheimer's disease (AD), and it is known that inflammation is associated with both aging and AD. To resolve inflammation, biosynthesis of the specialized pro-resolving mediators (SPMs) is enhanced in a programmed and active manner. We investigated the effect of age on resolution by analyzing hippocampal tissue from 2- and 9-month-old senescence-accelerated mouse prone 8 (SAMP8), as well as age-matched senescence-accelerated mouse resistant 1 (SAMR1). Pro-inflammatory markers increased upon age in SAMP8 mice and were also higher than those in age-matched SAMR1 mice. However, neither SPMs nor their receptors were enhanced upon age in SAMP8 mice compared to age-matched SAMR1 mice. Analysis of SPM biosynthetic enzymes revealed elevated levels of leukocyte type 12-lipoxygenase (L12-LOX) and decreased 5-LOX levels upon age in SAMR1 mice, whereas they remained unchanged in SAMP8 mice. Moreover, we found partial co-localization of L12-LOX and amyloid beta (Aß) staining, as well as correlation between L12-LOX and phosphorylated tau levels in SAMP8, but not SAMR1 mice. Thus, we conclude that the resolution response in SAMP8 mice is insufficient to counteract the increased inflammation with age, and this may have a role in the development of AD-like pathologies.