Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Jan 13.
Published in final edited form as: Neurosci Lett. 2022 Oct 18;791:136921. doi: 10.1016/j.neulet.2022.136921

Probing changes in brain esterified oxylipin concentrations during the early stages of pathogenesis in Alzheimer’s Disease transgenic rats

Qing Shen 1, Kelley T Patten 2, Anthony Valenzuela 2, Pamela J Lein 2,3,4, Ameer Y Taha 1,4,5,*
PMCID: PMC9839422  NIHMSID: NIHMS1856874  PMID: 36270451

Abstract

Despite known pathological hallmarks of Alzheimer’s Disease (AD) including neuronal loss, gliosis (inflammation), beta-amyloid plaque deposition and neurofibrillary tangle accumulation in the brain, little is known about inflammation resolution in early AD pathogenesis. In the brain, inflammation and resolution are mediated by free oxylipins which are mostly bound (i.e. esterified), and therefore must be released (i.e. become free) to exert bioactivity. Recently, we showed reductions in brain esterified pro-resolving oxylipins in a transgenic rat model of AD (TgF344-AD rat) at 15 months of age, suggesting deficits in the source and availability of free pro-resolving oxylipins. In the present study, we tested whether these changes are discernable earlier in the disease process, i.e., at age of 10 months. We observed significant reductions in esterified pro-resolving 8(9)-epoxyeicosatrienoic acid (8(9)-EpETrE), 13-hydroxy-octadecatrienoic acid (13-HOTrE) and 15-hydroxy-eicosapentaenoic acid (15-HEPE) and in pro-inflammatory 13-hydroxy-octadecadienoic acid (13-HODE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 15-deoxy-prostaglandin J2 (15-deoxy-PGJ2) and prostaglandin E2 (PGE2) in male and/or female transgenic AD rats compared to wildtype controls. These findings point to a deficit in esterified pro-resolving lipid mediators in the early stages of AD. Changes in esterified pro-inflammatory lipid mediators were confined to a few compounds between time-points, possibly due to enhanced engagement of resolution pathways with disease progression.

Keywords: Alzheimer’s Disease, rat brain, esterified oxylipins, inflammation resolution, lipid mediator

1. Introduction

Alzheimer’s Disease (AD) is an incurable progressive brain disorder that affects more than 11% of individuals above the age of 65 [1]. AD is characterized by age-dependent changes in mood and cognition, amyloid and tau accumulation in the brain, and microglial activation and astrocytosis characteristic of neuroinflammation (reviewed in [14]).

In a pathologically normal brain, inflammation is kept at bay through an active resolution process enabled by ‘pro-resolving’ lipid mediators (i.e. oxylipins) enzymatically derived from polyunsaturated fatty acids. Enzymes involved in lipid mediator synthesis are lipoxygenase (LOX), cyclooxygenase (COX), cytochrome P450 (CYP), soluble epoxide hydrolase (sEH) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (Reviewed in [9]). Oxylipins can have both pro-inflammatory and pro-resolving effects in vivo [9]. For instance, arachidonic acid (AA)-derived hydroxyeicosatetraenoic acids (HETEs) and prostanoids (e.g. prostaglandin E2) are known to promote inflammation, whereas epoxides of AA, eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) promote the resolution of inflammation.

It is thought that unresolved inflammation in the brain contributes to AD worsening over time [6, 11, 19, 29, 31, 32, 34, 35]. This is evidenced by studies in human cerebrospinal fluid and post-mortem brain, as well as transgenic mouse models showing that in AD, pro-inflammatory lipid mediators such as HETEs and dihydroxyeicosatrienoic acids (DiHETrEs) are elevated [8, 20, 26, 29, 31, 33, 35], whereas pro-resolving oxylipins (neuroprotectin D1, maresin 1, lipoxin A4 (LXA4), epoxydocosapentaenoic acids (EpDPEs), and epoxyeicosatrienoic acids (EpETrEs) ) are reduced compared to unaffected controls [6, 11, 19, 29, 31, 32, 34, 35]. Collectively, the evidence points to impaired lipid-mediated resolution pathways in AD, concomitant with persistent inflammation.

To date, studies have measured free (unesterified) pro-resolving oxylipins in the brain of transgenic mice modelling some aspects of AD pathology in humans, and in postmortem brain of AD patients [6, 11, 19, 29, 31, 32, 34, 35]. Yet, in the brain, the majority of oxylipins (~90%) are bound (i.e. esterified) to neutral lipids (NLs) such as triacylglycerols and cholesteryl esters, and to membrane phospholipids (PLs) [23, 30]. The esterified oxylipin pool serves as an important modulator of free oxylipin concentrations via a turnover pathway which releases and re-esterifies free oxylipins [23]. This turnover pathway regulates the in vivo bioavailability of free oxylipins, which is the bioactive pool that mediates inflammation and inflammation resolution [22, 27]. In contrast, esterified oxylipins are less biologically active, despite serving as a source or reservoir for free oxylipins [16, 21].

Our group has found that pro-resolving lipid mediators are selectively and markedly reduced within brain esterified lipid pools of transgenic AD female rats expressing mutations in the human Swedish amyloid precursor protein (APPswe) and exon 9 presenilin-1 (PS1ΔE9) [28]. Because esterified oxylipins regulate free oxylipin bioavailability, our findings point to sex-specific deficits in the source of free pro-resolving oxylipins in AD. This is in agreement with studies showing reduced concentrations of free pro-resolving oxylipins in the brain of AD patients and transgenic animal models of AD [6, 11, 19, 29, 31, 32, 34, 35].

In our prior work involving AD transgenic rats, we measured esterified pro-resolving oxylipins in 15-month old animals [28], when AD pathology and behavioral impairments were established [25]. In the present study, we tested whether changes in esterified oxylipins are discernable earlier in the disease process. Mass-spectrometry was used to quantify NL- and PL-bound oxylipins in whole brain of 10-month-old animals because at that age, AD transgenic rats show no signs of cognitive impairment or phosphorylated tau accumulation in the brain [25], but present with evidence of beta-amyloid deposition and microglial activation, although less compared to 15 month old animals [25]. Both male and female rats were tested to determine whether sex differences in oxylipin metabolism exist, in view of our prior observations showing changes in esterified oxylipins in AD transgenic rat females but not males, and the higher epidemiological prevalence of AD in females compared to males [3, 7].

2. Material and methods

2.1. Animals

Animal protocols were approved by the University of California, Davis (UC Davis) Institutional Animal Care and Use Committee (IACUC). The overall experimental design is shown in Supplementary Figure 1. Male and female transgenic AD rats (TgF344-AD) and wildtype littermates (WTF344) were bred at UC Davis [25] and the resulting offspring consisting of 26 male and female TgF344-AD and WTF344 rats were transferred on postnatal day 28, to a tunnel facility in Northern California [10], where they received filtered air. This subset of animals was part of a broader study examining the effects of traffic-related air pollution on AD phenotypes in rats [10, 25]. We focused the present analysis on AD and wildtype (WT) rats exposed to filtered air only. Rats were transported back to UC Davis after 9 months. They were euthanized 2 days later with 4% isoflurane (Southmedic Inc., Barrie ON) and brain samples were harvested [25].

2.2. Brain NL and PL oxylipin analysis

Esterified oxylipins were extracted from the right hemisphere with 6 mL of 2:1 chloroform/methanol and 700 μL aqueous buffer containing 1 mM Na2EDTA and 0.9% NaCl, followed by a repeated 4 mL of chloroform extraction, as previously described [28]. The total lipid extract was reconstituted and a 300 μL volume containing ~3 mg total lipids was subjected to solid phase extraction (SPE) on Waters silica columns (Sep-Pak Silica, 1 cc, 100 mg, Waters Corporation, Milford, MA; Cat #WAT023595) preconditioned with methanol (1.5 mL) and 2:1 v/v chloroform/isopropanol (1.5 mL). NLs were eluted with 1.5 mL of chloroform/isopropanol (2:1 v/v). The silica column was washed 1.5 mL of 95% methanol, and the eluent containing PLs was adjusted to 80% methanol and then loaded onto Waters tC18 columns (Sep-Pak tC18, 1 cc, 100 mg, Cat #WAT036820) preconditioned with one column volume of methanol and 1.5 mL of 80% methanol. The column was washed with 2 mL of 80% methanol, followed by 2 mL pure methanol to elute PLs.

NL and PL fractions were reconstituted in 200 μL of methanol containing 0.1% acetic acid and 0.1% butylated hydroxytoluene (BHT), 10 μL of antioxidant solution (0.2 mg/mL BHT, ethylenediaminetetraacetic acid and triphenylphosphine in 1:1 water/methanol), 10 μL of 2 μM surrogate standard mix (of d11-11(12)-EpETrE, d11-14,15-DiHETrE, d4-6-keto-PGF1a, d4-9-HODE, d4-LTB4, d4- PGE2, d4- thromboxane B2 (TXB2), d6-20-HETE, and d8-5-HETE in LC-MS grade methanol), and 200 μL of 0.25 M NaOH in 1:1 water/methanol. The mixture was vortexed, hydrolyzed at 60°C for 30 minutes on a heating block and cooled at room temperature for ~5 min. The reaction was stopped with 25 μL of acetic acid and 1575 μL of MilliQ water. Samples were loaded onto Waters Oasis HLB columns (3 cc, 60 mg, 30 μm particle size; Waters Corporation, Cat #WAT094226) pre-rinsed with one column volume of ethyl acetate and two volumes of methanol, and preconditioned with two column volumes of SPE buffer containing 0.1% acetic acid and 5% methanol in MilliQ water. Upon loading the samples, the columns were washed with two column volumes of SPE buffer, dried under vacuum (≈15–20 psi) for 20 min. Oxylipins were eluted with 0.5 mL methanol and 1.5 mL ethyl acetate into 2 mL centrifuge tubes, reconstituted in 100 μL LCMS grade methanol, and filtered using 0.1 μm Centrifugal Filters (Millipore Sigma, Burlington, MA, USA; Cat # UFC30VV00).

A total of 76 oxylipins per lipid pool were analyzed by ultra high-pressure liquid chromatography-tandem mass spectrometry as previously described [28].

2.3. Statistical analysis

GraphPad Prism v.8.02 (La Jolla, CA, USA) software was used for data analysis. Missing oxylipin values (up to 3 per group) were imputed by dividing the lowest observable concentration on the standard curve by the square root of 2. The number of imputed oxylipin values per group is shown in Supplementary Table 1.

The effects of sex and genotype on brain NL and PL oxylipins were examined by two-way analysis of variance (ANOVA). The effects of genotype on brain NL and PL oxylipins per sex were determined by an unpaired Student’s t-test followed by Benjamini and Hochberg correction at a false discovery rate (FDR) of 1%, given the small sample size (6–8 per group per sex) and preliminary nature of the study [4]. Statistically significant values were accepted at p<0.05 and at q <0.01.

3. Results

3.1. Effects of AD genotype on NL-bound oxylipins in brain of 10-month-old rats

Two-way ANOVA showed that sex was a significant factor affecting linoleic acid (LA)-derived 9-octadecadienoic acid (9-oxo-ODE), AA-derived 15-HETE, LXA4 and prostaglandin F2a (PGF2a), EPA-derived 15-hydroxyeicosapentaenoic acid (15-HEPE), and DHA-derived 17-hydroxydocosahexaenoic acid (17-HDoHE), 19(20)-EpDPE, 16(17)-EpDPE and 7(8)-EpDPE in brain NLs, which were 18%−102% higher in females than males (p < 0.05; Supplementary Table 2).

Genotype significantly altered EPA-derived 15-HEPE, and DHA-derived 16,17-dihydroxydocosapentaenoic acid (16,17-DiHDPA) (p < 0.05; Supplementary Table 2). 15-HEPE was lower by 14% in AD transgenic rats compared to WT controls (Figure 1-a), whereas 16,17-DiHDPA was 49% higher in AD versus WT rats, irrespective of sex (Figure 1-b).

Figure 1.

Figure 1.

Open in a new tab

Oxylipin concentrations (pmol/g) in brain neutral lipids (NLs) of 10-month-old wildtype (WT) and TgF344-AD (Tg) female and male rats: (a) 15 hydroxy-eicosapentaenoic acid (15-HEPE); (b) 16,17-dihydroxy-docosapentaenoic acid (16,17-DiHDPA); (c) 13-hydroxy-octadecadienoic acid (13-HODE); (d) 15-deoxy-prostaglandin J2 (15-deoxy- PGJ2). Female WT (n=6), female Tg (n=6), male WT (n=8), male Tg (n=6). Two-way ANOVA revealed significant effects of genotype on 15-HEPE and 16,17-DiHDPA, and a significant interaction between genotype and sex on 13-HODE and 15-deoxy-PGJ2. An asterisk (*) between the dashed line and solid line on top of some of the graphs denotes significance at p<0.05 by two-way ANOVA irrespective of sex. Two Asterisks (**) between bars comparing two groups denote significance at p<0.05 and q<0.01 by unpaired t-test with false discovery rate (FDR) correction per sex.

Significant sex and genotype interaction effects were observed in LA-derived 13-hydroxyoctadecadienoic acid (13-HODE), and AA-derived 20-HETE, 15-oxo-eicosatetraenoic acid (15-oxo-ETE) and 15-deoxy-prostaglandin J2 (15-deoxy-PGJ2) (p < 0.05; Supplementary Table 2). A main genotype effect was also observed for 15-deoxy-PGJ2 (p < 0.05; Supplementary Table 2).

Post-hoc comparison of AD versus WT rats, per sex, by unpaired Student’s t-test with FDR correction revealed a 35% reduction in LA-derived 13-HODE in TgF344-AD males compared to WT males (Figure 1-c, p=0.0022, q=0.0044) and a 48% reduction in AA-derived 15-deoxy-PGJ2 in TgF344-AD females compared to WT females (Figure 1-d, p=0.0021, q=0.0043). No significant differences per sex were observed for 20-HETE and 15-oxo-ETE by post-hoc comparison by unpaired t-test with FDR correction (Supplementary Table 2).

3.2. Effects of AD genotype on PL-bound oxylipins in brain of 10-month-old rats

Two-way ANOVA showed that sex was a significant factor affecting LA-derived 12(13)-epoxyoctadecenoic acid (12(13)-EpOME) and 9(10)-EpOME, dihomo-gamma-linoleic acid (DGLA)-derived 15(S)-hydroxyeicosatrienoic acid (15(S)-HETrE), AA-derived 14(15)-EpETrE, 11(12)-EpETrE, 8(9)-EpETrE, 5(6)-EpETrE, 11,12-dihydroxyeicosatrienoic acid (11,12-DiHETrE), 8,9-DiHETrE and LXA4, alpha-linolenic acid (ALA)-derived 13-hydroxyoctadecatrienoic acid (13-HOTrE), EPA-derived 14(15)- epoxyeicosatetraenoic acid (14(15)-EpETE) and Resolvin E1, and DHA-derived 19(20)-EpDPE, 16(17)-EpDPE, 13(14)-EpDPE, 7(8)-EpDPE and 19,20-DiHDPA in brain PLs (p < 0.05; Supplementary Table 3). These compounds were 24%−800% higher in females than males.

Genotype significantly altered AA-derived 20-HETE (Figure 2-a), 8(9)-EpETrE (Figure 2-b) and prostaglandin E2 (PGE2; Figure 2-c), and ALA-derived 13-HOTrE (Figure 2-d), which were all lower by 11–49% in AD compared to WT rats, irrespective of sex (p < 0.05; Supplementary Table 3).

Figure 2.

Figure 2.

Open in a new tab

Oxylipin concentrations (pmol/g) in brain phospholipid (PLs) of 10-month-old wildtype (WT) or TgF344-AD (Tg) female and male rats: (a) 20-hydroxy-eicosatetraenoic acid (20-HETE); (b) 8(9)-epoxy-eicosatrienoic acid (8(9)-EpETrE); (c) prostaglandin E2 (PGE2); (d) 13-hydroxy-octadecatrienoic acid (13-HOTrE); (e)16,17-dihydroxy-docosapentaenoic acid (16,17-DiHDPA). Two-way ANOVA revealed significant effects of genotype on 20-HETE, 8(9)-EpETrE, PGE2, and 13-HOTrE, and a significant sex and genotype interaction on 16,17-DiHDPA. Female WT (n=6), female Tg (n=6), male WT (n=8), male Tg (n=6). An asterisk (*) between the dashed line and solid line on top of some of the graphs denotes significance at p<0.05 by two-way ANOVA irrespective of sex. Two Asterisks (**) between bars comparing two groups denote significance at p<0.05 and q<0.01 by unpaired t-test with false discovery rate (FDR) correction per sex.

A significant sex and genotype interaction was observed in EPA-derived 11(12)-EpETE, and DHA-derived 16,17-DiHDPA (p < 0.05; Supplementary Table 3). Post-hoc unpaired t-test with FDR correction analysis of the groups per sex revealed significant differences in 16,17-DiHDPA but not 11(12)-EpETE concentrations. DHA-derived 16,17-DiHDPA was 37% lower in TgF344-AD males compared to WT males (Figure 2-e, p=0.0037, q=0.0074); no significant differences were observed in females.

4. Discussion

This study provides evidence of sex-specific brain changes in esterified lipid mediators involved in inflammation and inflammation resolution in 10-month old AD transgenic rats, coincident with the onset of microglial activation and β-amyloid plaque accumulation [25]. We observed significant reductions in both pro-resolving (AA-derived 8(9)-EpETrE, ALA-derived 13-HOTrE and EPA-derived 15-HEPE) and pro-inflammatory (AA-derived 20-HETE, 15-deoxy-PGJ2 and PGE2, and LA-derived 13-HODE) esterified oxylipins in male and/or female transgenic AD rats compared to WT controls. DHA-derived 16,17-DiHDPA, a diol fatty acid metabolite of pro-resolving 16(17)-EpDPE, was elevated in NLs of both sexes and reduced in PLs of 10-month old male AD rats.

The reduction in esterified pro-resolving lipid mediators at 10 months reflects early impairments in resolution pathways. Esterified oxylipins are a source of free and bioactive pro-resolving oxylipins [23] which halt inflammation [13, 22] and promote neuronal survival [5, 34] and axonal outgrowth [2] via specialized G-protein coupled receptors [16, 18]. Thus, reductions in esterified pro-resolving oxylipins are likely due to increased utilization (i.e. release via lipase enzymes) and turnover into free bioactive oxylipins that might contribute to inflammation resolution during the early phases of the disease. In the later phases of the disease, as more esterified pro-resolving lipid reserves become depleted [28], the availability of free pro-resolving oxylipins may decrease, consistent with studies showing reduced levels of free AA-derived epoxides (EpETrEs) in transgenic mouse models of AD after disease pathology is established [6, 11, 29].

A few pro-inflammatory oxylipins derived from omega-6 LA (13-HODE) and AA (20-HETE, 15-deoxy-PGJ2 and PGE2) decreased in brain esterified lipid pools of AD rats compared to WT controls at 10 months. These changes may be due to increased release or reduced esterification of free pro-inflammatory lipid mediators, coincident with inflammation seen in the brain of these animals at 10 months of age [25]. Studies have shown elevated free PGE2 concentrations in cerebrospinal fluid of AD patients [8, 20], although temporal changes in free PGE2 and other lipid mediators in this transgenic rodent model of AD remain to be confirmed.

DHA-derived 16,17-DiHDPA, an sEH product of 16(17)-EpDPE, was elevated in NLs of both sexes and reduced in PLs of 10-month-old male AD rats. It is possible that in males, 16,17-DiHDPA in PLs was remodeled into NLs, which could explain the increase seen there. Another explanation for the increase in NL-bound 16,17-DiHDPA is increased esterification, secondary to elevated sEH activation. sEH itself is not known to esterify oxylipins directly, but increased sEH activity reported in transgenic animal models of AD [29] may lead to excess free fatty acid diols which can then be sequestered into esterified lipids via acyl-CoA synthetase and acyltransferase enzymes [15, 17].

Of the lipid mediators that changed at 10 months, only PL-bound 8(9)-EpETrE and PGE2 overlapped and paralleled the reductions seen at 15 months in AD rats [28]. Additionally, 15-HEPE decreased in NLs at 10 months and in PLs at 15 months, whereas 20-HETE decreased in PLs at 10 months and in NLs at 15 months [28]. Collectively, these data reflect a progressive decline in esterified pro-resolving (8(9)-EpETrE and 15-HEPE) and pro-inflammatory (PGE2 and 20-HETE) lipid mediators with time, albeit within different esterified lipid pools in some cases possibly due PL/NL remodeling. Of note, many of the changes in esterified oxylipins at 15 months were seen in pro-resolving species [28], unlike pro-inflammatory lipid mediators which were confined to a few compounds between time-points, possibly due to enhanced engagement of resolution pathways with disease progression.

In AD transgenic rats, significant reductions in a few esterified oxylipins were seen at 10 months compared to 15 months of age (reductions in 8 oxylipins at 10 months versus 22 oxylipins at 15 months) [28]. These changes may be associated with temporal changes in disease progression. For instance, 15-month old TgF344-AD rats had more amyloid plaque deposition, higher hyperphosphorylated tau levels, more neuronal cell loss, and greater cognitive deficits than 10-month old rats [25]. It is difficult to establish which pathogenic factors altered esterified lipid mediators at 10 months. However, it appears that both the lipid mediators and pathology worsened over time. Future studies should explore whether blocking changes in esterified lipid mediator levels alter the progression of AD pathologies and cognitive impairment in transgenic AD rats.

Surprisingly, more changes in AD males were observed at 10 versus 15 months [28]. Specifically, NL-bound 13-HODE and PL-bound 16,17-DiHDPA were reduced in AD males at 10 months, but not at 15 months. It is not clear why the changes in males were transient. Males are more resilient to AD pathogenic changes than females. For instance, female transgenic AD rats exhibit Aβ proteinopathy earlier than males, and also show greater microglial activation relative to males [25]. In humans, females have twice the risk of AD compared to males [3, 24]. It is possible that adaptive mechanisms in esterified oxylipin turnover in males may explain sex differences in disease resiliency and progression.

The main limitation of this study is that free oxylipins were not measured. We did not elect to do so because unlike esterified oxylipins, free oxylipins are sensitive to the effects of postmortem ischemia. For instance, a 155-fold increase in brain free oxylipin concentrations was reported following post-mortem ischemia [12] compared to a 27–112% increase in esterified oxylipins [23]. Another limitation is that the hydrolysis procedure for liberating esterified oxylipins results in the destruction of some oxylipins such as prostaglandins [30]. Although this limits quantitation, relative differences would still be valid. In this study, key pathological and behavioral hallmarks of AD were not measured in rats, thus limiting our ability to directly correlate the lipid changes to AD-phenotypes.

In conclusion, we showed early-onset reductions in 4 pro-resolving lipid mediators or their diol metabolite, and 4 pro-inflammatory oxylipins within PLs and/or NLs in 10-months old transgenic AD rats. With age, more pro-resolving lipid mediators were reduced in esterified lipid pools of AD rats [28]. Age-dependent reductions in pro-resolving esterified lipid mediators may contribute to impaired resolution of inflammation in AD.

Supplementary Material

supplement

Acknowledgments:

This work was funded by the Alzheimer’s Association (2018-AARGD-591676) and the National Institutes of Health (R21 ES026515, R21 ES025570, P30 ES023513, and P30 AG010129). KTP was supported by NIH-funded predoctoral training programs awarded to the University of California, Davis (T32 MH112507 and T32 ES007059).

The authors thank Christopher Wallis for assistance with the animal colony, and Keith Bein and Tony Wexler for their help and guidance with the tunnel facility.

Footnotes

Conflicts of interest:

The authors declare no conflict of interest.

References:

  • [1].2021 Alzheimer’s disease facts and figures, Alzheimer’s & dementia : the journal of the Alzheimer’s Association 17 (2021) 327–406. [DOI] [PubMed] [Google Scholar]
  • [2].Abdu E, Bruun DA, Yang D, Yang J, Inceoglu B, Hammock BD, Alkayed NJ, Lein PJ, Epoxyeicosatrienoic acids enhance axonal growth in primary sensory and cortical neuronal cell cultures, Journal of Neurochemistry 117 (2011) 632–642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A, Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group, Neurology 53 (1999) 1992–1997. [DOI] [PubMed] [Google Scholar]
  • [4].Benjamini Y, Hochberg Y, Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing, Journal of the Royal Statistical Society: Series B (Methodological) 57 (1995) 289–300. [Google Scholar]
  • [5].Calandria JM, Sharp MW, Bazan NG, The Docosanoid Neuroprotectin D1 Induces TH-Positive Neuronal Survival in a Cellular Model of Parkinson’s Disease, Cellular and Molecular Neurobiology 35 (2015) 1127–1136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Chen W, Wang M, Zhu M, Xiong W, Qin X, Zhu X, 14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer’s Disease, The Journal of Neuroscience 40 (2020) 8188–8203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T, A Transgenic Alzheimer Rat with Plaques, Tau Pathology, Behavioral Impairment, Oligomeric Aβ, and Frank Neuronal Loss, The Journal of Neuroscience 33 (2013) 6245–6256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Combrinck M, Williams J, De Berardinis MA, Warden D, Puopolo M, Smith AD, Minghetti L, Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer’s disease, Journal of Neurology, Neurosurgery & Psychiatry 77 (2006) 85–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Dyall SC, Balas L, Bazan NG, Brenna JT, Chiang N, da Costa Souza F, Dalli J, Durand T, Galano JM, Lein PJ, Serhan CN, Taha AY, Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions, Prog Lipid Res 86 (2022) 101165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Edwards S, Zhao G, Tran J, Patten KT, Valenzuela A, Wallis C, Bein KJ, Wexler AS, Lein PJ, Rao X, Pathological Cardiopulmonary Evaluation of Rats Chronically Exposed to Traffic-Related Air Pollution, Environ Health Perspect 128 (2020) 127003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Ghosh A, Comerota MM, Wan D, Chen F, Propson NE, Hwang SH, Hammock BD, Zheng H, An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease, Science Translational Medicine 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Hennebelle M, Metherel AH, Kitson AP, Otoki Y, Yang J, Lee KSS, Hammock BD, Bazinet RP, Taha AY, Brain oxylipin concentrations following hypercapnia/ischemia: effects of brain dissection and dissection time, Journal of lipid research 60 (2019) 671–682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Inceoglu B, Jinks SL, Ulu A, Hegedus CM, Georgi K, Schmelzer KR, Wagner K, Jones PD, Morisseau C, Hammock BD, Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways, Proceedings of the National Academy of Sciences 105 (2008) 18901–18906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT, Inflammation as a central mechanism in Alzheimer’s disease, Alzheimers Dement (N Y) 4 (2018) 575–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Klett EL, Chen S, Yechoor A, Lih FB, Coleman RA, Long-chain acyl-CoA synthetase isoforms differ in preferences for eicosanoid species and long-chain fatty acids, Journal of lipid research 58 (2017) 884–894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Lahvic JL, Ammerman M, Li P, Blair MC, Stillman ER, Fast EM, Robertson AL, Christodoulou C, Perlin JR, Yang S, Chiang N, Norris PC, Daily ML, Redfield SE, Chan IT, Chatrizeh M, Chase ME, Weis O, Zhou Y, Serhan CN, Zon LI, Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132, Proceedings of the National Academy of Sciences 115 (2018) 9252–9257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Liu G-Y, Moon SH, Jenkins CM, Sims HF, Guan S, Gross RW, Synthesis of oxidized phospholipids by sn-1 acyltransferase using 2–15-HETE lysophospholipids, Journal of Biological Chemistry 294 (2019) 10146–10159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Liu X, Qian Z.-y., Xie F, Fan W, Nelson JW, Xiao X, Kaul S, Barnes AP, Alkayed NJ, Functional screening for G protein-coupled receptor targets of 14,15-epoxyeicosatrienoic acid, Prostaglandins & Other Lipid Mediators 132 (2017) 31–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Lukiw WJ, Cui J-G, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG, A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease, J Clin Invest 115 (2005) 2774–2783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Montine T, Sidell K, Crews B, Markesbery W, Marnett L, Roberts L, Morrow J, Elevated CSF prostaglandin E2 levels in patients with probable AD, Neurology 53 (1999) 1495–1495. [DOI] [PubMed] [Google Scholar]
  • [21].Obinata H, Hattori T, Nakane S, Tatei K, Izumi T, Identification of 9-Hydroxyoctadecadienoic Acid and Other Oxidized Free Fatty Acids as Ligands of the G Protein-coupled Receptor G2A *, Journal of Biological Chemistry 280 (2005) 40676–40683. [DOI] [PubMed] [Google Scholar]
  • [22].Orr SK, Palumbo S, Bosetti F, Mount HT, Kang JX, Greenwood CE, Ma DWL, Serhan CN, Bazinet RP, Unesterified docosahexaenoic acid is protective in neuroinflammation, Journal of Neurochemistry 127 (2013) 378–393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Otoki Y, Metherel AH, Pedersen T, Yang J, Hammock BD, Bazinet RP, Newman JW, Taha AY, Acute Hypercapnia/Ischemia Alters the Esterification of Arachidonic Acid and Docosahexaenoic Acid Epoxide Metabolites in Rat Brain Neutral Lipids, Lipids 55 (2020) 7–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Ott A, Breteler MMB, F.v. Harskamp, T. Stijnen, A. Hofman, Incidence and Risk of Dementia: The Rotterdam study, American Journal of Epidemiology 147 (1998) 574–580. [DOI] [PubMed] [Google Scholar]
  • [25].Patten KT, Valenzuela AE, Wallis C, Berg EL, Silverman JL, Bein KJ, Wexler AS, Lein PJ, The Effects of Chronic Exposure to Ambient Traffic-Related Air Pollution on Alzheimer’s Disease Phenotypes in Wildtype and Genetically Predisposed Male and Female Rats, Environmental Health Perspectives 129 (2021) 057005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Praticò D, Zhukareva V, Yao Y, Uryu K, Funk CD, Lawson JA, Trojanowski JQ, Lee VMY, 12/15-Lipoxygenase Is Increased in Alzheimer’s Disease: Possible Involvement in Brain Oxidative Stress, The American Journal of Pathology 164 (2004) 1655–1662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Shaik JSB, Ahmad M, Li W, Rose ME, Foley LM, Hitchens TK, Graham SH, Hwang SH, Hammock BD, Poloyac SM, Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke, Am J Physiol Heart Circ Physiol 305 (2013) H1605–H1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Shen Q, Liang N, Patten KT, Otoki Y, Valenzuela AE, Wallis C, Bein KJ, Wexler AS, Lein PJ, Taha AY, Pro-resolving Lipid Mediators Within Brain Esterified Lipid Pools are Reduced in Female Rats Chronically Exposed to Traffic-Related Air Pollution or Genetically Susceptible to Alzheimer’s Disease Phenotype, bioRxiv (2022) 2022.2002.2016.480656. [Google Scholar]
  • [29].Sun CP, Zhang XY, Zhou JJ, Huo XK, Yu ZL, Morisseau C, Hammock BD, Ma XC, Inhibition of sEH via stabilizing the level of EETs alleviated Alzheimer’s disease through GSK3β signaling pathway, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 156 (2021) 112516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Taha AY, Hennebelle M, Yang J, Zamora D, Rapoport SI, Hammock BD, Ramsden CE, Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid, Prostaglandins, leukotrienes, and essential fatty acids 138 (2018) 71–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Tajima Y, Ishikawa M, Maekawa K, Murayama M, Senoo Y, Nishimaki-Mogami T, Nakanishi H, Ikeda K, Arita M, Taguchi R, Okuno A, Mikawa R, Niida S, Takikawa O, Saito Y, Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease, Lipids in Health and Disease 12 (2013) 68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Wang Y, Li F, Zhuang H, Li L, Chen X, Zhang J, Effects of plant polyphenols and alpha-tocopherol on lipid oxidation, microbiological characteristics, and biogenic amines formation in dry-cured bacons, J Food Sci 80 (2015) C547–555. [DOI] [PubMed] [Google Scholar]
  • [33].Yao Y, Clark CM, Trojanowski JQ, Lee VM-Y, Praticò D, Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment, Annals of Neurology 58 (2005) 623–626. [DOI] [PubMed] [Google Scholar]
  • [34].Zhao Y, Calon F, Julien C, Winkler JW, Petasis NA, Lukiw WJ, Bazan NG, Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer’s Disease Models, PLOS ONE 6 (2011) e15816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Zhu M, Wang X, Hjorth E, Colas RA, Schroeder L, Granholm AC, Serhan CN, Schultzberg M, Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis, Molecular neurobiology 53 (2016) 2733–2749. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplement
NIHMS1856874-supplement-supplement.docx (185.9KB, docx)

RESOURCES