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Aging Alters Lipid Mediator Biosynthesis from Polyunsaturated Fatty Acids in the Brain of Senescence-Accelerated Mice with Age-Related Cognitive Dysfunction

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Aging Alters Lipid Mediator Biosynthesis from Polyunsaturated Fatty Acids in the Brain of Senescence-Accelerated Mice with Age-Related Cognitive Dysfunction June 2020 Medical Mass Spectrometry Vol. 4 No. 1 Research Paper Aging alters lipid mediator biosynthesis from polyunsaturated fatty acids in the brain of senescence-accelerated mice with age-related cognitive dysfunction Hideyuki Sasaki1,3*, Yoshihisa Kaneda1, Tomohiro Rogi1, Hiroshi Shibata1, Ryohei Aoyagi2, Tsuyoshi Yamane3, Kazutaka Ikeda3, Makoto Arita2,3 1 Institute for Health Care Science, Suntory Wellness Ltd., 8‒1‒1 Seikadai, Seika-cho, Soraku-gun, Kyoto 619‒0284, Japan 2 Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, 1‒5‒30 Shibakoen, Minato-ku, Tokyo 105‒8512, Japan 3 Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, 1‒7‒22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230‒0045, Japan Abstract This study aimed to clarify whether long-chain polyunsaturated fatty acid (LCPUFA) metabolism in the brain that causes an age-related decline of cognitive function changes with aging. The senescence-accelerated mice-prone 10 (SAMP10) is an animal model used in studies related to aging. Young (two-month-old) mice and aged (nine-month-old) mice were fed control diet for 12 weeks. Age-related changes in lipid mediator profiles in the cortex and hippocampus were assessed by comprehensive lipidomics, using liquid chromatography-tandem mass spectrometry after memory examination. The expression of fatty acid metabolism-related mRNAs was evaluated in the hippocampus. Free arachidonic acid (ARA) levels were extremely high among all detected free fatty acids, being approximately 8-fold higher than those of free DHA in the cortex and hippocampus of both young and aged mice. Level of ARA-derived metabolites was extraordinarily high compared to that of other PUFA-derived metabolites, whereas that of DHA-derived metabolites was very low in the cortex and hippocampus of both mice. Aging decreased ARA-derived metabolites in the hippocampus, regardless of the biosyn- thetic pathway, such as cyclooxygenase, 5-lipoxygenase, 12/15-lipoxygenase, cytochrome P450, and non-enzymatic autox- idation. DHA-derived metabolites in the hippocampus were also decreased by age. There was no significant difference in mRNA expression of the various enzymes related to metabolite biosynthesis between young and aged mice. The cognitive function of SAMP10 was impaired due to aging. Based on analyzing a board range of LCPUFA-derived metabolites, we propose that age-related decrease in LCPUFA metabolism in the hippocampus may be involved in the impaired cognitive function in SAMP10 mice. Key words: senescence-accelerated mice, polyunsaturated fatty acids, lipid mediator, brain Introduction Long-chain polyunsaturated fatty acids (LCPUFAs) are the main constituents of biomembranes. They consist of * Corresponding author two series, namely n-6 and n-3. The major n-6 LCPUFA is Hideyuki Sasaki arachidonic acid (ARA), while the major n-3 LCPUFAs are Institute for Health Care Science, Suntory Wellness Ltd., 8‒1‒ docosahexaenoic acid (DHA) and eicosapentaenoic acid 1 Seikadai, Seika-cho, Soraku-gun, Kyoto 619‒0284, Japan ‒ ‒ Tel: ＋81‒50‒3182‒0683, Fax: ＋81‒774‒98‒6262 (EPA). They have 20 22 carbons with 4 6 double bonds, E-mail: [email protected] and play important roles in physiological homeostasis, Received: February 27, 2020. Accepted: March 26, 2020. including the modulation of membrane fluidity, membrane 1,2) Epub May 21, 2020. enzyme activities, and physiological responses . DOI: 10.24508/mms.2020.06.005 Some of these responses are induced by the formation of 65 June 2020 Medical Mass Spectrometry Vol. 4 No. 1 lipid mediators from LCPUFAs themselves. These lipid expression-associated metabolism of LCPUFA in the brain mediators have been shown to exert a range of biological of young and aged SAMP10 mice. effects. The 2-series prostaglandins and 4-series leukot- rienes, biosynthesized from ARA, are well-known lipid Materials and Methods mediators that are generally involved in the initiation of Animals and diets acute inflammation. On the other hand, lipid mediators All protocols for animal procedures were approved by derived from EPA and DHA, such as the 3-series prosta- the Ethics Committee of Animal Experiment in accordance glandins, 5-series leukotrienes, resolvins, protectin, and with the Internal Regulations on Animal Experiments at maresin, exhibit anti-inflammatory effects. The biosynthesis Suntory, which are based on the Law for the Humane Treat- of LCPUFA-derived lipid mediators is mainly evoked by ment and Management of Animals (Law No. 105, 1 Octo- cyclooxygenase (COX), lipoxygenase (LOX), and cyto- ber 1973, as amended in 2 June 2017). Male SAMP10 mice chrome P450 (CYP) enzymes. Lipid mediators are also par- were obtained from Japan SLC, Inc. (Shizuoka, Japan). tially produced through non-enzymatic autoxidation mecha- They were housed individually in polycarbonate cages with nisms3,4). Recently, some studies have shown new paper bedding, which was changed once a week. The facil- physiological functions of several metabolites. For ity was maintained under specific pathogen-free conditions instance, 18-hydroxyeicosapentaenoic acid derived from at a temperature of 23±2°C and humidity of 55±10%, with EPA inhibits proinflammatory activation of cardiac fibro- a 12-h light/dark cycle (light was switched on at 7:00). blasts5), and DHA-derived protectin D1 (PD1) remarkably Before the experiment, mice were acclimated to the facility attenuates influenza virus replication and improves the sur- for more than a week. The mice had free access to water vival and pathology of severe influenza in mice6). and feed; we used the latter based on AIN-93M containing LCPUFAs are the major components of brain phospho- 4% fat with modified lipid compositions. The lipids con- lipids and their levels in humans7) and animals8) have been sisted of palm oil, soybean oil, and linseed oil (SHOWA reported to decrease with aging. DHA/EPA or ARA supple- KOSAN CO., LTD., Minato-ku, Tokyo, Japan). The fatty mentation has been shown to improve the cognitive func- acid compositions of the diet are shown in Table 1. All the tion in healthy elderly humans9,10), and ameliorate the diets were stored at 4°C and changed twice a week to pre- reduced cognitive function in aged animals as well11,12). vent oxidation. After more than 1 week of acclimation Various mechanisms, such as synaptic plasticity, neurogen- period, SAMP10 mice aged 2 or 9 months were fed the diet esis, and membrane fluidity have been shown to be associ- for 12 weeks, and we measured weight once a week and ated with this effect in aged animals2,11). A few metabolites, observed general appearance twice a week. such as PGE2 and PD1, have been shown to improve brain function13,14), though the relationship between lipid metabo- Gas–liquid chromatography (GC) for fatty acid com- lites and brain function still remains unclear. Moreover, position non-reported study has examined the changes in LCPUFA Lipids in the diet were extracted and purified by the metabolite profiles in the brain with age-related impairment of cognitive function. Table 1. Fatty acid composition of the diet The current study aimed to clarify changes in LCPUFA FA (AIN93M contained 4% fat) (%) metabolism in the brain, which may be involved in an Palmitic acid (PA) 26.9 age-related decline of cognitive function. SAMP10 strain Stearic acid (SA) 4.3 was selected as a model of age-related neurodegeneration, Oleic acid (OA) 31.2 - exhibiting age related cerebral atrophy due to the loss and Linoleic acid (LA) 22.5 15) perikaryal shrinkage of cortical neurons . Aged SAMP10 α-Linolenic acid (ALA) 11.3 mice have a more deteriorated cognitive function than Dihomo-γ-linolenic acid (DGLA) 0.0 SAMR1 control mice. In the present study, we investigated Arachidonic acid (ARA) 0.0 137 molecular species of free fatty acids and metabolites by Eicosapentaenoic acid (EPA) 0.0 comprehensive lipidomics systems using liquid chromatog- Docosahexaenoic acid (DHA) 0.0 Others 3.7 raphy-tandem mass spectrometry (LC-MS/MS), and mRNA 66 June 2020 Medical Mass Spectrometry Vol. 4 No. 1 16) method of Folch et al . Phospholipids, which were d8, 15-HETE-d8, LTB4-d4, and PGE2-d4, respectively. obtained using thin-layer chromatography (hexane : diethyl ether＝7 : 3), were methylesterified by incubating in methan- RNA sequencing olic HCl at 50°C for 3 h, extracted with hexane, and sub- Total RNA was isolated from brain tissues using jected to capillary gas‒liquid chromatography (Agilent ISOGEN (Nippon Gene, Tokyo, Japan) and purified using 7890B; Agilent Technologies, Santa Clara, CA) using an the RNeasy Mini kit (QIAGEN, Hilden, Germany) in SP-2330 column (30 m×0.32 mm×0.2μ m; Supelco, Belle- accordance with the manufacturer’s instructions, as previ- fonte, PA) with He (at 30 cm/s) as the carrier. The column ously described19). The integrity of isolated RNA was deter- temperature was initially 180°C for 2 min and then mined using a bioanalyzer (Agilent Technologies, Santa increased to 220°C at a rate of 2°C/min. Clara, CA, USA). RNA integrity numbers (RIN) of all sam- ples were identified higher than 8.6 and five samples were LC-MS/MS analysis for lipidomics in brain samples selected in order of higher RIN value for library prepara- Brain tissues were homogenized on ice with methanol, tion and sequencing, for each young and aged mouse. The and the extracted lipids were purified in solid-phase using mRNA library preparation was based on SureSelect Sep-Pak C18 3 cc Vac cartridges (Waters) with deuteri- Strand-Specific RNA Library Prep for Illumina Multiplexed um-labeled internal standards (IS; AA-d8, 15-HETE-d8, Sequencing (Agilent Technologies, version C.0, December 14,15-EET-d11, PGE2-d4, and LTB4-d4, each at a final con- 2014). RNA-seq libraries were sequenced on a HiSeq 1500 centration of 10 pg/μL), excluding the sample that one hip- DNA Sequencer (Illumina, San Diego, CA, USA) in a pocampus of the aged mice could not be extracted lipids.
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