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Iso-α-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer's Disease*

  • Yasuhisa Ano
    Correspondence
    To whom correspondence should be addressed: Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., 1-13-5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan.
    Affiliations
    Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., Kanagawa 236-0004, Japan
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  • Atsushi Dohata
    Affiliations
    Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan
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  • Yoshimasa Taniguchi
    Affiliations
    Central Laboratories for Key Technologies, Kirin Company Ltd., Kanagawa 236-0004, Japan
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  • Ayaka Hoshi
    Affiliations
    Central Laboratories for Key Technologies, Kirin Company Ltd., Kanagawa 236-0004, Japan
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  • Kazuyuki Uchida
    Affiliations
    Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan
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  • Akihiko Takashima
    Affiliations
    Department of Neurobiology, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan
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  • Hiroyuki Nakayama
    Affiliations
    Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan
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  • Author Footnotes
    * This work was supported by a Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-aid Project, Scientific Research on Innovation Area (Brain Protein Aging and Dementia control (to A. T.)) and by Japan Agency for Medical Research and Development (AMED) DEMENTIA Research and Development Project 16dk0207026h0301 (to A. T.). The authors declare that they have no conflicts of interest with the contents of this article.
Open AccessPublished:January 13, 2017DOI:https://doi.org/10.1074/jbc.M116.763813
      Alongside the rapid growth in aging populations worldwide, prevention and therapy for age-related memory decline and dementia are in great demand to maintain a long, healthy life. Here we found that iso-α-acids, hop-derived bitter compounds in beer, enhance microglial phagocytosis and suppress inflammation via activation of the peroxisome proliferator-activated receptor γ. In normal mice, oral administration of iso-α-acids led to a significant increase both in CD11b and CD206 double-positive anti-inflammatory type microglia (p < 0.05) and in microglial phagocytosis in the brain. In Alzheimer's model 5xFAD mice, oral administration of iso-α-acids resulted in a 21% reduction in amyloid β in the cerebral cortex as observed by immunohistochemical analysis, a significant reduction in inflammatory cytokines such as IL-1β and chemokines including macrophage inflammatory protein-1α in the cerebral cortex (p < 0.05) and a significant improvement in a novel object recognition test (p < 0.05), as compared with control-fed 5xFAD mice. The differences in iso-α-acid-fed mice were due to the induction of microglia to an anti-inflammatory phenotype. The present study is the first to report that amyloid β deposition and inflammation are suppressed in a mouse model of Alzheimer's disease by a single component, iso-α-acids, via the regulation of microglial activation. The suppression of neuroinflammation and improvement in cognitive function suggests that iso-α-acids contained in beer may be useful for the prevention of dementia.

      Introduction

      With the rapid growth in aged populations, cognitive decline and dementia are becoming an increasing burden not only on patients and their families, but also on national healthcare systems worldwide. Because of the lack of a disease-modifying therapy for dementia, preventive approaches such as diet, exercise, and learning are being explored. In etiological studies of lifestyle, for example, low to moderate consumption of alcohol, such as wine and beer, might reduce the risk of developing dementia (
      • Matsui T.
      • Yoshimura A.
      • Toyama T.
      • Matsushita S.
      • Higuchi S.
      Preventive effect of moderation in drinking on dementia.
      ,
      • Neafsey E.J.
      • Collins M.A.
      Moderate alcohol consumption and cognitive risk.
      • Horvat P.
      • Richards M.
      • Kubinova R.
      • Pajak A.
      • Malyutina S.
      • Shishkin S.
      • Pikhart H.
      • Peasey A.
      • Marmot M.G.
      • Singh-Manoux A.
      • Bobak M.
      Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults.
      ). Individuals who consumed low to moderate levels of alcoholic beverages on a daily basis were shown to have significantly lower risk of the development of cardiovascular and neurodegenerative disease, as compared with individuals who abstained from alcohol beverages or drank heavily. Apart from the effects of alcohol itself, resveratrol, a polyphenolic compound in red wine, has neuroprotective (
      • Arntzen K.A.
      • Schirmer H.
      • Wilsgaard T.
      • Mathiesen E.B.
      Moderate wine consumption is associated with better cognitive test results: a 7 year follow up of 5033 subjects in the Tromsø Study.
      ,
      • Porquet D.
      • Griñán-Ferré C.
      • Ferrer I.
      • Camins A.
      • Sanfeliu C.
      • Del Valle J.
      • Pallàs M.
      Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer's disease.
      • Witte A.V.
      • Kerti L.
      • Margulies D.S.
      • Flöel A.
      Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults.
      ) and cardioprotective (
      • Vidavalur R.
      • Otani H.
      • Singal P.K.
      • Maulik N.
      Significance of wine and resveratrol in cardiovascular disease: French paradox revisited.
      ,
      • Petrovski G.
      • Gurusamy N.
      • Das D.K.
      Resveratrol in cardiovascular health and disease.
      ) activities. On the other hand, beer has remained the most consumed alcoholic beverage in the world for more than a thousand years, and hops, the female inflorescences of the hop plant (Humulus lupulus L.), have been used in beer-brewing since 822; to date, however, no constituents of beer have been reported to be beneficial for preventing dementia.
      Hops are used as both a preservative and a flavoring agent in the beer-brewing process. The bitter taste of beer originates from α-acids in hops. Because iso-α-acids activate the peroxisome proliferator-activated receptor-γ (PPAR-γ)
      The abbreviations used are: PPAR-γ
      peroxisome proliferator-activated receptor-γ
      IAA
      iso-α-acids
      amyloid β
      MIP-1α
      macrophage inflammatory protein-1α
      tIH
      trans-isohumulone
      cIH
      cis-isohumulone
      FAD
      familial Alzheimer's disease
      FAM
      fluorescein amidite
      IHE
      isomerized hop extract
      MACS
      magnetic cell sorting
      PDL
      poly-d-lysine
      ANOVA
      analysis of variance.
      (
      • Yajima H.
      • Ikeshima E.
      • Shiraki M.
      • Kanaya T.
      • Fujiwara D.
      • Odai H.
      • Tsuboyama-Kasaoka N.
      • Ezaki O.
      • Oikawa S.
      • Kondo K.
      Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor α and γ and reduce insulin resistance.
      • Yajima H.
      • Noguchi T.
      • Ikeshima E.
      • Shiraki M.
      • Kanaya T.
      • Tsuboyama-Kasaoka N.
      • Ezaki O.
      • Oikawa S.
      • Kondo K.
      Prevention of diet-induced obesity by dietary isomerized hop extract containing isohumulones, in rodents.
      ,
      • Namikoshi T.
      • Tomita N.
      • Fujimoto S.
      • Haruna Y.
      • Ohzeki M.
      • Komai N.
      • Sasaki T.
      • Yoshida A.
      • Kashihara N.
      Isohumulones derived from hops ameliorate renal injury via an anti-oxidative effect in Dahl salt-sensitive rats.
      • Cho Y.C.
      • You S.K.
      • Kim H.J.
      • Cho C.W.
      • Lee I.S.
      • Kang B.Y.
      Xanthohumol inhibits IL-12 production and reduces chronic allergic contact dermatitis.
      ), iso-α-acids in beer have antioxidant and anti-metabolic syndrome activities and are also reported to prevent diet-induced obesity in rodents and to improve hyperglycemia, which has also been confirmed in humans (
      • Obara K.
      • Mizutani M.
      • Hitomi Y.
      • Yajima H.
      • Kondo K.
      Isohumulones, the bitter component of beer, improve hyperglycemia and decrease body fat in Japanese subjects with prediabetes.
      ). PPAR-γ is known as a therapeutic target in Alzheimer disease (

      Agarwal, S., Yadav, A., and Chaturvedi, R., (2016) K peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun., in press

      ), which prompted us to study the effects of iso-α-acids, as beer components, on the pathogenesis of Alzheimer's disease.
      In the present study, we examined whether, as agonists of PPAR-γ, the iso-α-acids present in beer might increase microglial phagocytosis of amyloid β (Aβ) and suppress inflammation in neuronal tissue. We also evaluated the ability of iso-α-acids to prevent Alzheimer's disease-like pathology and cognitive decline in a mouse model of Alzheimer's disease.

      Discussion

      The present study has identified a novel physiological function of iso-α-acids, constituents of hops used in beer making, in the prevention of Alzheimer's disease-like symptoms by enhancing microglial phagocytosis, suppressing inflammation, and improving cognitive function. All six stereoisomers of the three iso-α-acid congeners enhanced microglial phagocytosis in cultured cells. In particular, trans-isohumulone and cis-isohumulone, both of which are plentiful in beer, had potent activity as compared with the other congeners.
      Iso-α-acids enhanced the surface expression of CD36, which mediates the innate host response to Aβ. CD36 is known to be involved in fatty acid metabolism, heart disease, taste, and dietary fat processing in the intestine (
      • Bonen A.
      • Campbell S.E.
      • Benton C.R.
      • Chabowski A.
      • Coort S.L.
      • Han X.X.
      • Koonen D.P.
      • Glatz J.F.
      • Luiken J.J.
      Regulation of fatty acid transport by fatty acid translocase/CD36.
      • Abumrad N.A.
      CD36 may determine our desire for dietary fats.
      ,
      • Moore K.J.
      • Kunjathoor V.V.
      • Koehn S.L.
      • Manning J.J.
      • Tseng A.A.
      • Silver J.M.
      • McKee M.
      • Freeman M.W.
      Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice.
      ,
      • Lynes M.D.
      • Widmaier E.P.
      Involvement of CD36 and intestinal alkaline phosphatases in fatty acid transport in enterocytes, and the response to a high-fat diet.
      ,
      • Samovski D.
      • Sun J.
      • Pietka T.
      • Gross R.W.
      • Eckel R.H.
      • Su X.
      • Stahl P.D.
      • Abumrad N.A.
      Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation.
      • Sundaresan S.
      • Abumrad N.A.
      Dietary lipids inform the gut and brain about meal arrival via CD36-mediated signal transduction.
      ). CD36 on the surface of microglia is reported to play an important role in Aβ phagocytosis in the brain; therefore, it is thought to be a potential preventive or therapeutic target for Alzheimer's disease (
      • Savill J.
      • Hogg N.
      • Ren Y.
      • Haslett C.
      Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis.
      ,
      • Yu Y.
      • Ye R.D.
      Microglial Aβ receptors in Alzheimer's disease.
      ). Our findings suggest that iso-α-acids enhance Aβ phagocytosis by increasing CD36 expression. Moreover, in mice given iso-α-acids orally, a transformation of CD11b-positive microglia to CD206-positive M2 anti-inflammatory type microglia was observed. Generally, type 1 microglia are involved in inflammation and M2 type in anti-inflammatory and tissue repairing processes (
      • Cherry J.D.
      • Olschowka J.A.
      • O'Banion M.K.
      Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.
      ,
      • Orihuela R.
      • McPherson C.A.
      • Harry G.J.
      Microglial M1/M2 polarization and metabolic states.
      • Tang Y.
      • Le W.
      Differential roles of M1 and M2 microglia in neurodegenerative diseases.
      ), suggesting that iso-α-acids stimulate both microglial phagocytosis and an anti-inflammatory phenotype. Microglia treated with iso-α-acids also showed enhanced intake of foreign substances other than Aβ. On the other hand, iso-α-acids had no effects on the production of Aβ by neurons (data not shown).
      Our group previously reported that iso-α-acids bind and activate PPAR-γ (
      • Yajima H.
      • Ikeshima E.
      • Shiraki M.
      • Kanaya T.
      • Fujiwara D.
      • Odai H.
      • Tsuboyama-Kasaoka N.
      • Ezaki O.
      • Oikawa S.
      • Kondo K.
      Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor α and γ and reduce insulin resistance.
      ). Activation of PPAR-γ, a nuclear receptor, contributes to the enhancement of microglial phagocytosis (
      • Mandrekar-Colucci S.
      • Karlo J.C.
      • Landreth G.E.
      Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease.
      • Yamanaka M.
      • Ishikawa T.
      • Griep A.
      • Axt D.
      • Kummer M.P.
      • Heneka M.T.
      PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
      ,
      • Ballesteros I.
      • Cuartero M.I.
      • Pradillo J.M.
      • de la Parra J.
      • Pérez-Ruiz A.
      • Corbí A.
      • Ricote M.
      • Hamilton J.A.
      • Sobrado M.
      • Vivancos J.
      • Nombela F.
      • Lizasoain I.
      • Moro M.A.
      Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARγ and 5-LO-dependent pathways.
      • Li X.
      • Melief E.
      • Postupna N.
      • Montine K.S.
      • Keene C.D.
      • Montine T.J.
      Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Aβ42 phagocytosis.
      ). PPAR-γ is known as a drug discovery target to improve resistance to insulin, and pioglitazone, a potent PPAR-γ agonist (
      • Olefsky J.M.
      • Saltiel A.R.
      PPARγ and the treatment of insulin resistance.
      ,
      • Olefsky J.M.
      Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists.
      ), is used to treat type 2 diabetes (
      • Murphy G.J.
      • Holder J.C.
      PPAR-γ agonists: therapeutic role in diabetes, inflammation and cancer.
      ). Blockade of PPAR-γ using an antagonist reduces the phagocytosis enhanced by iso-α-acids. Activation of PPAR-γ has anti-diabetes, anti-arterial sclerosis, anti-tumor, and anti-inflammation effects (
      • Jiang C.
      • Ting A.T.
      • Seed B.
      PPAR-γ agonists inhibit production of monocyte inflammatory cytokines.
      ,
      • Panigrahy D.
      • Huang S.
      • Kieran M.W.
      • Kaipainen A.
      PPARγ as a therapeutic target for tumor angiogenesis and metastasis.
      • Schmidt M.V.
      • Brüne B.
      • von Knethen A.
      The nuclear hormone receptor PPARγ as a therapeutic target in major diseases.
      ), and pro-phagocytic effects on Aβ (
      • Yamanaka M.
      • Ishikawa T.
      • Griep A.
      • Axt D.
      • Kummer M.P.
      • Heneka M.T.
      PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
      ). Recently, PPAR-γ has been considered a potential preventive or therapeutic target for Alzheimer's disease (

      Agarwal, S., Yadav, A., and Chaturvedi, R., (2016) K peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun., in press

      ). Here, iso-α-acids were found to reduce the levels of Aβ and inflammatory cytokines and to improve cognitive function in 5xFAD model mice via PPAR-γ activation.
      Iso-α-acids from hops are plentiful in beer, providing bitter flavor at a concentration of about 20–40 mg/liter, and have been consumed for more than a thousand years. The safety of iso-α-acids was confirmed both in tests using rodents and in human studies. Our group previously reported that administration of iso-α-acids led to an improvement of hyperglycemia and a decrease in body fat in humans. Between 16 and 48 mg of iso-α-acids were administered in the experiment, and a dose of 32–48 mg significantly reduced fasting blood glucose in humans (
      • Obara K.
      • Mizutani M.
      • Hitomi Y.
      • Yajima H.
      • Kondo K.
      Isohumulones, the bitter component of beer, improve hyperglycemia and decrease body fat in Japanese subjects with prediabetes.
      ). The doses in that report were based on a study of anti-obesity effects using C57BL/6 mice (
      • Yajima H.
      • Noguchi T.
      • Ikeshima E.
      • Shiraki M.
      • Kanaya T.
      • Tsuboyama-Kasaoka N.
      • Ezaki O.
      • Oikawa S.
      • Kondo K.
      Prevention of diet-induced obesity by dietary isomerized hop extract containing isohumulones, in rodents.
      ). The amount of iso-α-acids given to 5xFAD mice in the present report was lower than that in the study of anti-obesity effects in mice. Therefore, it is expected that a dose of less than 32–48 mg of iso-α-acids would have beneficial effects on neuroprotection in humans. In summary, because iso-α-acids suppress neuroinflammation and improve cognitive function, they may be useful for the prevention of dementia.

      Author Contributions

      Y. A. conducted most of the experiments, analyzed the results, and wrote most of the paper. H. N., K. U., and A. D. conducted experiments on 5xFAD mice. Y. T. and A. H. conducted the experiment for the LC/MS/MS analysis of iso-α-acids. A. T. conducted experiments on anti-inflammation and wrote the manuscript.

      Acknowledgment

      We acknowledge Dr. M. Okamura for assistance in the preparation of the manuscript.

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