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Consumption of Grape Seed Extract Prevents Amyloid-β Deposition and Attenuates Inflammation in Brain of an Alzheimer’s Disease Mouse

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Abstract

Polyphenols extracted from grape seeds are able to inhibit amyloid-beta (Aβ) aggregation, reduce Aβ production and protect against Aβ neurotoxicity in vitro. We aimed to investigate the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in Alzheimer’s disease (AD) mice. APPSwe/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid (49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and proanthocyanidins (436.6 mg catechin equivalents/g). Long-term feeding of GSE diet was well tolerated without fatality, behavioural abnormality, changes in food consumption, body weight or liver function. The Aβ levels in the brain and serum of the mice fed with GSE were reduced by 33% and 44%, respectively, compared with the Alzheimer’s mice fed with the control diet. Amyloid plaques and microgliosis in the brain of Alzheimer’s mice fed with GSE were also reduced by 49% and 70%, respectively. Curcumin also significantly reduced brain Aβ burden and microglia activation. Conclusively, polyphenol-rich GSE prevents the Aβ deposition and attenuates the inflammation in the brain of a transgenic mouse model, and this thus is promising in delaying development of AD.

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References

  • Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, Morris C, Winblad B, Nordberg A, Zhu J (2002) Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice. J Neuroimmunol 126:50–57

    Article  PubMed  CAS  Google Scholar 

  • Akiyama H et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  PubMed  CAS  Google Scholar 

  • Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alperovitch A (2007) Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69:1921–1930

    Article  PubMed  CAS  Google Scholar 

  • Bastianetto S, Zheng WH, Quirion R (2000) Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. Br J Pharmacol 131:711–720

    Article  PubMed  CAS  Google Scholar 

  • Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202:17–20

    Article  PubMed  CAS  Google Scholar 

  • Bralley EE, Hargrove JL, Greenspan P, Hartle DK (2007) Topical anti-inflammatory activities of Vitis rotundifolia (muscadine grape) extracts in the tetradecanoylphorbol acetate model of ear inflammation. J Med Food 10:636–642

    Article  PubMed  CAS  Google Scholar 

  • Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimer Dementia 3:186–191

    Article  Google Scholar 

  • Citron M (2004) Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci 5:677–685

    Article  PubMed  CAS  Google Scholar 

  • Deshane J, Chaves L, Sarikonda KV, Isbell S, Wilson L, Kirk M, Grubbs C, Barnes S, Meleth S, Kim H (2004) Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem 52:7872–7883

    Article  PubMed  CAS  Google Scholar 

  • El-Agnaf OM, Mahil DS, Patel BP, Austen BM (2000) Oligomerization and toxicity of beta-amyloid-42 implicated in Alzheimer’s disease. Biochem Biophys Res Commun 273:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G (1991) Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett 129:318–320

    Article  PubMed  CAS  Google Scholar 

  • Food and Drug Administration (2003) Guidance for industry and reviewers. estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers. Fed Regist 68:2340–2341

    Google Scholar 

  • Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524

    Article  PubMed  CAS  Google Scholar 

  • Greenrod W, Fenech M (2003) The principal phenolic and alcoholic components of wine protect human lymphocytes against hydrogen peroxide- and ionizing radiation-induced DNA damage in vitro. Mutagenesis 18:119–126

    Article  PubMed  CAS  Google Scholar 

  • Greenrod W, Stockley CS, Burcham P, Abbey M, Fenech M (2005) Moderate acute intake of de-alcoholized red wine, but not alcohol, is protective against radiation-induced DNA damage ex vivo - results of a comparative in vivo intervention study in younger men. Mutat Res 591:290–301

    PubMed  CAS  Google Scholar 

  • Hampl JS, Anderson JV, Mullis R (2002) Position of the American Dietetic Association: the role of dietetics professionals in health promotion and disease prevention. J Am Diet Assoc 102:1680–1687

    Article  PubMed  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  • Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91

    Article  PubMed  CAS  Google Scholar 

  • Jang JH, Surh YJ (2003) Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free Radic Biol Med 34:1100–1110

    Article  PubMed  CAS  Google Scholar 

  • Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–165

    Article  PubMed  CAS  Google Scholar 

  • Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697

    Article  PubMed  CAS  Google Scholar 

  • Jekabsone A, Mander PK, Tickler A, Sharpe M, Brown GC (2006) Fibrillar beta-amyloid peptide Abeta1–40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflammation 3:24

    Article  PubMed  CAS  Google Scholar 

  • Kalin R, Righi A, Del Rosso A, Bagchi D, Generini S, Cerinic MM, Das DK (2002) Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in systemic sclerosis. Free Radic Res 36:819–825

    Article  PubMed  CAS  Google Scholar 

  • Kammerer D, Claus A, Carle R, Schieber A (2004) Polyphenol screening of pomace from red and white grape varieties (Vitis vinifera L.) by HPLC-DAD-MS/MS. J Agric Food Chem 52:4360–4367

    Article  PubMed  CAS  Google Scholar 

  • Kim SJ, Jeong HJ, Lee KM, Myung NY, An NH, Yang WM, Park SK, Lee HJ, Hong SH, Kim HM, Um JY (2007) Epigallocatechin-3-gallate suppresses NF-kappaB activation and phosphorylation of p38 MAPK and JNK in human astrocytoma U373MG cells. J Nutr Biochem 18:587–596

    Article  PubMed  CAS  Google Scholar 

  • Lau FC, Shukitt-Hale B, Joseph JA (2005) The beneficial effects of fruit polyphenols on brain aging. Neurobiol Aging 26(Suppl. 1):128–132

    Article  PubMed  CAS  Google Scholar 

  • Letenneur L (2004) Risk of dementia and alcohol and wine consumption: a review of recent results. Biol Res 37:189–193

    PubMed  Google Scholar 

  • Levites Y, Amit T, Mandel S, Youdim MB (2003) Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (−)-epigallocatechin-3-gallate. FASEB J 17:952–954

    PubMed  CAS  Google Scholar 

  • Li WG, Zhang XY, Wu YJ, Tian X (2001) Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds. Acta Pharmacol Sin 22:1117–1120

    PubMed  CAS  Google Scholar 

  • Li MH, Jang JH, Sun B, Surh YJ (2004) Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death. Ann NY Acad Sci 1030:317–329

    Article  PubMed  CAS  Google Scholar 

  • Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377

    PubMed  CAS  Google Scholar 

  • Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I (2002) Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156:445–453

    Article  PubMed  Google Scholar 

  • Ma L, Gao HQ, Li BY, Ma YB, You BA, Zhang FL (2007) Grape seed proanthocyanidin extracts inhibit vascular cell adhesion molecule expression induced by advanced glycation end products through activation of peroxisome proliferators-activated receptor gamma. J Cardiovasc Pharmacol 49:293–298

    Article  PubMed  CAS  Google Scholar 

  • Mancuso C, Bates TE, Butterfield DA, Calafato S, Cornelius C, Lorenzo AD, Dinkova Kostova AT, Calabrese V (2007) Natural antioxidants in Alzheimer’s disease. Expert Opin Investig Drugs 16:1921–1931

    Article  PubMed  CAS  Google Scholar 

  • Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280:37377–37382

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2007) NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 28:639–647

    Article  PubMed  CAS  Google Scholar 

  • Mehlhorn G, Hollborn M, Schliebs R (2000) Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int J Dev Neurosci 18:423–431

    Article  PubMed  CAS  Google Scholar 

  • Meme W, Calvo CF, Froger N, Ezan P, Amigou E, Koulakoff A, Giaume C (2006) Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. FASEB J 20:494–496

    PubMed  CAS  Google Scholar 

  • Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87:172–181

    Article  PubMed  CAS  Google Scholar 

  • Ono K, Hasegawa K, Naiki H, Yamada M (2005) Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun 330:111–116

    Article  PubMed  CAS  Google Scholar 

  • Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D, Salamon R, Renaud S, Breteler MB (1997) Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris) 153:185–192

    CAS  Google Scholar 

  • Reeves PG (1997) Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr 127:838S–841S

    PubMed  CAS  Google Scholar 

  • Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25:8807–8814

    Article  PubMed  CAS  Google Scholar 

  • Reznichenko L, Amit T, Zheng H, Avramovich-Tirosh Y, Youdim MB, Weinreb O, Mandel S (2006) Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (−)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer’s disease. J Neurochem 97:527–536

    Article  PubMed  CAS  Google Scholar 

  • Riviere C, Richard T, Vitrac X, Merillon JM, Valls J, Monti JP (2007) New polyphenols active on beta-amyloid aggregation. Bioorg Med Chem Lett 18(2):828–831

    Article  PubMed  CAS  Google Scholar 

  • Savaskan E, Olivieri G, Meier F, Seifritz E, Wirz-Justice A, Muller-Spahn F (2003) Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology 49:380–383

    Article  PubMed  CAS  Google Scholar 

  • Sharma SD, Meeran SM, Katiyar SK (2007) Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling in in vivo SKH-1 hairless mice. Mol Cancer Ther 6:995–1005

    Article  PubMed  CAS  Google Scholar 

  • Shi J, Yu J, Pohorly JE, Kakuda Y (2003) Polyphenolics in grape seeds-biochemistry and functionality. J Med Food 6:291–299

    Article  PubMed  CAS  Google Scholar 

  • Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C, Wharton SB (2008) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging [Epub ahead of print]

  • Sly LM, Krzesicki RF, Brashler JR, Buhl AE, McKinley DD, Carter DB, Chin JE (2001) Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer’s disease. Brain Res Bull 56:581–588

    Article  PubMed  CAS  Google Scholar 

  • Solerte SB, Cravello L, Ferrari E, Fioravanti M (2000) Overproduction of IFN-gamma and TNF-alpha from natural killer (NK) cells is associated with abnormal NK reactivity and cognitive derangement in Alzheimer’s disease. Ann NY Acad Sci 917:331–340

    Article  PubMed  CAS  Google Scholar 

  • Thomas P, Fenech M (2007) A review of genome mutation and Alzheimer’s disease. Mutagenesis 22:15–33

    Article  PubMed  CAS  Google Scholar 

  • Thomas P, Wang YJ, Zhong JH, Kosaraju S, O'Callaghan NJ, Zhou XF, Fenech M (2008) Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer's disease. Mutat Res (in press)

  • Vinson JA, Mandarano MA, Shuta DL, Bagchi M, Bagchi D (2002) Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a niacin-bound chromium in a hamster atherosclerosis model. Mol Cell Biochem 240:99–103

    Article  PubMed  CAS  Google Scholar 

  • von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 12:215–232

    Article  Google Scholar 

  • Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti GM (2006a) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer’s disease. FASEB J 20:2313–2320

    Article  PubMed  CAS  Google Scholar 

  • Wang YJ, Zhou HD, Zhou XF (2006b) Clearance of amyloid-beta in Alzheimer’s disease: progress, problems and perspectives. Drug Discov Today 11:931–938

    Article  PubMed  CAS  Google Scholar 

  • Wang YJ, Pollard AN, Zhou HD, Zhong JH, Zhou XF (2006c) Characterization of an Alzheimer ‘s disease mouse model bearing mutant genes of amyloid precursor protein and human presenilin. In: Proceedings of the Australian Neuroscience Society (Sydney), p 150

  • Wang YJ, Pollard A, Zhong JH, Dong XY, Wu XB, Zhou HD, Zhou XF (2009) Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer’s disease. Neurobiol Aging 30:364–376

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB, Pasinetti GM (2008) Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 28:6388–6392

    Article  PubMed  CAS  Google Scholar 

  • World Health Organization (2003) World Health Report 2003-Shaping the future. WHO, Geneva

  • Yamakoshi J, Saito M, Kataoka S, Kikuchi M (2002) Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem Toxicol 40:599–607

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170:680–692

    Article  PubMed  CAS  Google Scholar 

  • Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid-beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank Dr Qiao-Xin Li and Professor Colin Masters from the Department of Pathology, the University of Melbourne for their advice and input. This work was supported by grants from the Australian Centre of Excellence for Functional Foods (MF) and Australian NHMRC (No. 480422, X. F. Zhou & Y. J. Wang). Y. J. Wang is supported by EIPRS at Flinders University.

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Authors and Affiliations

  1. Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, SA, Australia

    Yan-Jiang Wang, Jin-Hua Zhong, Fang-Fang Bi, Anthony Pollard & Xin-Fu Zhou

  2. Australian Commonwealth Scientific and Research Organization (CSIRO) Human Nutrition, P.O. Box 10041, Adelaide BC, Adelaide, SA, Australia

    Philip Thomas & Michael Fenech

  3. CSIRO Food Science Australia, 671 Snydes Rd, Private Bag 16, Werribee, VIC, 3030, Australia

    Shantha Kosaraju

  4. Department of Neurology, Chongqing Daping Hospital, Third Military Medical University, Chongqing, 400042, China

    Yan-Jiang Wang

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  1. Yan-Jiang Wang
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  2. Philip Thomas
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  3. Jin-Hua Zhong
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  4. Fang-Fang Bi
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  8. Xin-Fu Zhou
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Correspondence to Michael Fenech or Xin-Fu Zhou.

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The authors Y.-J. Wang and P. Thomas contributed equally to this work.

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Wang, YJ., Thomas, P., Zhong, JH. et al. Consumption of Grape Seed Extract Prevents Amyloid-β Deposition and Attenuates Inflammation in Brain of an Alzheimer’s Disease Mouse. Neurotox Res 15, 3–14 (2009). https://doi.org/10.1007/s12640-009-9000-x

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