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Current Nutrition Reports

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Open Access 01-06-2018 | Neurological Disease and Cognitive Function (Y Gu, Section Editor)

Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration

Authors: Emma Flanagan, Michael Müller, Michael Hornberger, David Vauzour

Published in: Current Nutrition Reports | Issue 2/2018

Abstract

Purpose of Review

This review summarises the most recent evidence regarding the effects of dietary flavonoids on age-related cognitive decline and neurodegenerative diseases.

Recent Findings

Recent evidence indicates that plant-derived flavonoids may exert powerful actions on mammalian cognition and protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects of flavonoids have been suggested to be due to interactions with the cellular and molecular architecture of brain regions responsible for memory.

Summary

Mechanisms for the beneficial effects of flavonoids on age-related cognitive decline and dementia are discussed, including modulating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus, bidirectional interactions with gut microbiota and attenuating the extracellular accumulation of pathological proteins. These processes are known to be important in maintaining optimal neuronal function and preventing age-related cognitive decline and neurodegeneration.

Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348(14):1356–64. https://doi.org/10.1056/NEJM2003ra020003.CrossRefPubMed

Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75 e2. https://doi.org/10.1016/j.jalz.2012.11.007.CrossRefPubMed

Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP. The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr. 2008;3(3–4):115–26. https://doi.org/10.1007/s12263-008-0091-4.CrossRefPubMedPubMedCentral

Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N. Food combination and Alzheimer disease risk: a protective diet. Arch Neurol. 2010;67(6):699–706. https://doi.org/10.1001/archneurol.2010.84.CrossRefPubMedPubMedCentral

Solfrizzi V, Panza F, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, et al. Diet and Alzheimer’s disease risk factors or prevention: the current evidence. Expert Rev Neurother. 2011;11(5):677–708. https://doi.org/10.1586/ern.11.56.CrossRefPubMed

Dixon RA, Wahlin A, Maitland SB, Hultsch DF, Hertzog C, Backman L. Episodic memory change in late adulthood: generalizability across samples and performance indices. Mem Cogn. 2004;32(5):768–78.CrossRef

Siedlecki KL, Salthouse TA, Berish DE. Is there anything special about the aging of source memory? Psychol Aging. 2005;20(1):19–32. https://doi.org/10.1037/0882-7974.20.1.19.CrossRefPubMed

Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, et al. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007;69(20):1921–30. https://doi.org/10.1212/01.wnl.0000278116.37320.52.CrossRefPubMed

Kesse-Guyot E, Fezeu L, Andreeva VA, Touvier M, Scalbert A, Hercberg S, et al. Total and specific polyphenol intakes in midlife are associated with cognitive function measured 13 years later. J Nutr. 2012;142(1):76–83. https://doi.org/10.3945/jn.111.144428.CrossRefPubMed

10.

Letenneur L, Proust-Lima C, Le GA, Dartigues JF, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165(12):1364–71.CrossRefPubMed

11.

Rothwell JA, Perez-Jimenez J, Neveu V, Medina-Remon A, M’Hiri N, Garcia-Lobato P, et al. Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content. Database (Oxford). 2013;2013:bat070. https://doi.org/10.1093/database/bat070.CrossRef

12.

Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med. 2008;45(3):295–305.CrossRefPubMed

13.

Goyarzu P, Malin DH, Lau FC, Taglialatela G, Moon WD, Jennings R, et al. Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci. 2004;7(2):75–83. https://doi.org/10.1080/10284150410001710410.CrossRefPubMed

14.

Barros D, Amaral OB, Izquierdo I, Geracitano L, Do Carmo Bassols Raseira M, Henriques AT, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol Biochem Behav. 2006;84(2):229–34. https://doi.org/10.1016/j.pbb.2006.05.001.CrossRefPubMed

15.

Ramirez MR, Izquierdo I, Do Carmo Bassols Raseira M, Zuanazzi JA, Barros D, Henriques AT. Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res. 2005;52(6):457–62.CrossRefPubMed

16.

Rendeiro C, Vauzour D, Kean RJ, Butler LT, Rattray M, Spencer JP, et al. Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats. Psychopharmacology. 2012;223(3):319–30. https://doi.org/10.1007/s00213-012-2719-8.CrossRefPubMed

17.

Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 2012; https://doi.org/10.1002/ana.23594.

18.

van Praag H, Lucero MJ, Yeo GW, Stecker K, Heivand N, Zhao C, et al. Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci. 2007;27(22):5869–78. https://doi.org/10.1523/JNEUROSCI.0914-07.2007.CrossRefPubMedPubMedCentral

19.

Li Q, Zhao HF, Zhang ZF, Liu ZG, Pei XR, Wang JB, et al. Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience. 2009;159(4):1208–15. https://doi.org/10.1016/j.neuroscience.2009.02.008.CrossRefPubMed

20.

Alzheimer’s A. 2012 Alzheimer’s disease facts and figures. Alzheimers Dement. 2012;8(2):131–68. https://doi.org/10.1016/j.jalz.2012.02.001.CrossRef

21.

Walsh DM, Teplow DB. Chapter 4 - Alzheimer’s disease and the amyloid β-protein. In: David BT, editor. Progress in molecular biology and translational science. Academic Press; 2012. p. 101–24.

22.

Petersen RC, Negash S. Mild cognitive impairment: an overview. CNS Spectr. 2008;13(1):45–53.CrossRefPubMed

23.

Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270–9. https://doi.org/10.1016/j.jalz.2011.03.008.CrossRefPubMedPubMedCentral

24.

Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia—meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 2009;119(4):252–65. https://doi.org/10.1111/j.1600-0447.2008.01326.x.CrossRefPubMed

25.

Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol. 2000;16(4):357–63.CrossRefPubMed

26.

Price DL, Tanzi RE, Borchelt DR, Sisodia SS. Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet. 1998;32:461–93. https://doi.org/10.1146/annurev.genet.32.1.461.CrossRefPubMed

27.

Jones L, Harold D, Williams J. Genetic evidence for the involvement of lipid metabolism in Alzheimer’s disease. Biochim Biophys Acta. 2010;1801(8):754–61. https://doi.org/10.1016/j.bbalip.2010.04.005.CrossRefPubMed

28.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.CrossRefPubMed

29.

Packard CJ, Westendorp RG, Stott DJ, Caslake MJ, Murray HM, Shepherd J, et al. Association between apolipoprotein E4 and cognitive decline in elderly adults. J Am Geriatr Soc. 2007;55(11):1777–85. https://doi.org/10.1111/j.1532-5415.2007.01415.x.CrossRefPubMed

30.

Whitehair DC, Sherzai A, Emond J, Raman R, Aisen PS, Petersen RC, et al. Influence of apolipoprotein E varepsilon4 on rates of cognitive and functional decline in mild cognitive impairment. Alzheimers Dement. 2010;6(5):412–9. https://doi.org/10.1016/j.jalz.2009.12.003.CrossRefPubMedPubMedCentral

31.

Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: the Kame Project. Am J Med. 2006;119(9):751–9. https://doi.org/10.1016/j.amjmed.2006.03.045.CrossRefPubMedPubMedCentral

32.

Field DT, Williams CM, Butler LT. Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol Behav. 2011;103(3–4):255–60. https://doi.org/10.1016/j.physbeh.2011.02.013.CrossRefPubMed

33.

Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol. 2010;24(10):1505–14. https://doi.org/10.1177/0269881109106923.CrossRefPubMed

34.

Lamport DJ, Pal D, Moutsiana C, Field DT, Williams CM, Spencer JP, et al. The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. Psychopharmacology. 2015;232(17):3227–34. https://doi.org/10.1007/s00213-015-3972-4.CrossRefPubMedPubMedCentral

35.

Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014;17(12):1798–803. https://doi.org/10.1038/nn.3850.CrossRefPubMedPubMedCentral

36.

Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br J Nutr. 2010;103(5):730–4. https://doi.org/10.1017/S0007114509992364.CrossRefPubMed

37.

Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, et al. Blueberry supplementation improves memory in older adults. J Agric Food Chem. 2010;58(7):3996–4000. https://doi.org/10.1021/jf9029332.CrossRefPubMedPubMedCentral

38.

Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study. Hypertension. 2012;60(3):794–801. https://doi.org/10.1161/HYPERTENSIONAHA.112.193060.CrossRefPubMed

39.

Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004;36(7):838–49. https://doi.org/10.1016/j.freeradbiomed.2004.01.001.CrossRefPubMed

40.

Savonenko AV, Melnikova T, Hiatt A, Li T, Worley PF, Troncoso JC, et al. Alzheimer’s therapeutics: translation of preclinical science to clinical drug development. Neuropsychopharmacology. 2012;37(1):261–77. https://doi.org/10.1038/npp.2011.211.CrossRefPubMed

41.

Walsh DM, Selkoe DJ. A beta oligomers—a decade of discovery. J Neurochem. 2007;101(5):1172–84. https://doi.org/10.1111/j.1471-4159.2006.04426.x.CrossRefPubMed

42.

Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, et al. Tannic acid is a natural beta-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem. 2012; https://doi.org/10.1074/jbc.M111.294025.

43.

Williams RJ, Spencer JP. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med. 2012;52(1):35–45. https://doi.org/10.1016/j.freeradbiomed.2011.09.010.CrossRefPubMed

44.

Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F, Jensen M, Runfeldt M, et al. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res. 2008;1214:177–87. https://doi.org/10.1016/j.brainres.2008.02.107.CrossRefPubMed

45.

Li Q, Zhao HF, Zhang ZF, Liu ZG, Pei XR, Wang JB, et al. Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Abeta1-42 oligomers and upregulating synaptic plasticity-related proteins in the hippocampus. Neuroscience. 2009;163(3):741–9. https://doi.org/10.1016/j.neuroscience.2009.07.014.CrossRefPubMed

46.

Ono K, Condron MM, Ho L, Wang J, Zhao W, Pasinetti GM, et al. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem. 2008;283(47):32176–87. https://doi.org/10.1074/jbc.M806154200.CrossRefPubMedPubMedCentral

47.

Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, et al. Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther. 2008;326(3):739–44. https://doi.org/10.1124/jpet.108.140293.CrossRefPubMed

48.

Amit T, Avramovich-Tirosh Y, Youdim MB, Mandel S. Targeting multiple Alzheimer’s disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. FASEB J. 2008;22(5):1296–305. https://doi.org/10.1096/fj.07-8627rev.CrossRefPubMed

49.

Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol. 2008;15(6):558–66. https://doi.org/10.1038/nsmb.1437.CrossRefPubMed

50.

Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart J, et al. ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 2006;281(24):16419–27. https://doi.org/10.1074/jbc.M600617200.CrossRefPubMed

51.

•• Dal-Pan A, Dudonne S, Bourassa P, Bourdoulous M, Tremblay C, Desjardins Y, et al. Cognitive-enhancing effects of a polyphenols-rich extract from fruits without changes in neuropathology in an animal model of Alzheimer’s disease. J Alzheimers Dis. 2017;55(1):115–35. https://doi.org/10.3233/JAD-160281. This study by Dal-Pan et al. (2017) showed that the consumption of polyphenol-rich extracts prevented memory impairment in an AD mouse model, and furthermore that these effects were observed in the absence of any direct impact on amyloid plaques or neurofibrillary tangles. These findings suggest that the protective benefits of flavonoids extend beyond interactions with classical AD neuropathology. CrossRefPubMed

52.

Schroeter H, Bahia P, Spencer JPE, Sheppard O, Rattray M, Rice-Evans C, et al. (-)-epicatechin stimulates ERK-dependent cyclic AMP response element activity and upregulates GLUR2 in cortical neurons. J Neurochem. 2007;101:1596–606.CrossRefPubMed

53.

Vauzour D, Vafeiadou K, Rice-Evans C, Williams RJ, Spencer JP. Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J Neurochem. 2007;103(4):1355–67. https://doi.org/10.1111/j.1471-4159.2007.04841.x.CrossRefPubMed

54.

Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxidative Med Cell Longev. 2012;2012:914273. https://doi.org/10.1155/2012/914273.CrossRef

55.

Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice-Evans C. MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging. 2002;23(5):861–80.CrossRefPubMed

56.

Schroeter H, Spencer JP, Rice-Evans C, Williams RJ. Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J. 2001;358(Pt 3):547–57.CrossRefPubMedPubMedCentral

57.

Vauzour D, VafeiAdou K, Rice-Evans C, Williams RJ, Spencer JP. Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J Neurochem. 2007;103(4):1355–67.CrossRefPubMed

58.

Levites Y, Youdim MB, Maor G, Mandel S. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol. 2002;63(1):21–9.CrossRefPubMed

59.

Impey S, Smith DM, Obrietan K, Donahue R, Wade C, Storm DR. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci. 1998;1(7):595–601. https://doi.org/10.1038/2830.CrossRefPubMed

60.

Tully T, Bourtchouladze R, Scott R, Tallman J. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov. 2003;2(4):267–77. https://doi.org/10.1038/nrd1061.CrossRefPubMed

61.

Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, et al. Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci. 2001;21(15):5484–93.CrossRefPubMedPubMedCentral

62.

Reznichenko L, Amit T, Youdim MB, Mandel S. Green tea polyphenol (-)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem. 2005;93(5):1157–67. https://doi.org/10.1111/j.1471-4159.2005.03085.x.CrossRefPubMed

63.

Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des. 2010;16(25):2766–78.CrossRefPubMed

64.

Calder PC, Albers R, Antoine JM, Blum S, Bourdet-Sicard R, Ferns GA, et al. Inflammatory disease processes and interactions with nutrition. Br J Nutr. 2009;101(Suppl 1):S1–45. https://doi.org/10.1017/S0007114509377867.PubMedCrossRef

65.

Trollor JN, Smith E, Baune BT, Kochan NA, Campbell L, Samaras K, et al. Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord. 2010;30(6):569–78. https://doi.org/10.1159/000322092.CrossRefPubMed

66.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421.CrossRefPubMedPubMedCentral

67.

Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull. 2003;61(3):255–60.CrossRefPubMed

68.

Kravitz BA, Corrada MM, Kawas CH. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old. Alzheimers Dement. 2009;5(4):318–23. https://doi.org/10.1016/j.jalz.2009.04.1230.CrossRefPubMedPubMedCentral

69.

Duong T, Nikolaeva M, Acton PJ. C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer’s disease. Brain Res. 1997;749(1):152–6.CrossRefPubMed

70.

Wood JA, Wood PL, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, et al. Cytokine indices in Alzheimer’s temporal cortex: no changes in mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res. 1993;629(2):245–52.CrossRefPubMed

71.

Roberts RO, Geda YE, Knopman DS, Boeve BF, Christianson TJ, Pankratz VS, et al. Association of C-reactive protein with mild cognitive impairment. Alzheimers Dement. 2009;5(5):398–405. https://doi.org/10.1016/j.jalz.2009.01.025.CrossRefPubMedPubMedCentral

72.

Zaciragic A, Lepara O, Valjevac A, Arslanagic S, Fajkic A, Hadzovic-Dzuvo A, et al. Elevated serum C-reactive protein concentration in Bosnian patients with probable Alzheimer’s disease. J Alzheimers Dis. 2007;12(2):151–6.CrossRefPubMed

73.

Williams P, Sorribas A, Howes MJ. Natural products as a source of Alzheimer’s drug leads. Nat Prod Rep. 2011;28(1):48–77. https://doi.org/10.1039/c0np00027b.CrossRefPubMed

74.

Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology. 2004;23(4):159–69. https://doi.org/10.1159/000078501.CrossRefPubMed

75.

Spencer JP, Vafeiadou K, Williams RJ, Vauzour D. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Asp Med. 2012;33(1):83–97. https://doi.org/10.1016/j.mam.2011.10.016.CrossRef

76.

Spilsbury A, Vauzour D, Spencer JP, Rattray M. Regulation of NF-kappaB activity in astrocytes: effects of flavonoids at dietary-relevant concentrations. Biochem Biophys Res Commun. 2012;418(3):578–83. https://doi.org/10.1016/j.bbrc.2012.01.081.CrossRefPubMed

77.

Vafeiadou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ, Spencer JP. The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys. 2009;484(1):100–9. https://doi.org/10.1016/j.abb.2009.01.016.CrossRefPubMed

78.

Nanri A, Yoshida D, Yamaji T, Mizoue T, Takayanagi R, Kono S. Dietary patterns and C-reactive protein in Japanese men and women. Am J Clin Nutr. 2008;87(5):1488–96.CrossRefPubMed

79.

Chun OK, Chung SJ, Claycombe KJ, Song WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr. 2008;138(4):753–60.CrossRefPubMed

80.

Karlsen A, Retterstol L, Laake P, Paur I, Bohn SK, Sandvik L, et al. Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. J Nutr. 2007;137(8):1951–4.CrossRefPubMed

81.

Widlansky ME, Duffy SJ, Hamburg NM, Gokce N, Warden BA, Wiseman S, et al. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic Biol Med. 2005;38(4):499–506. https://doi.org/10.1016/j.freeradbiomed.2004.11.013.CrossRefPubMed

82.

Freese R, Vaarala O, Turpeinen AM, Mutanen M. No difference in platelet activation or inflammation markers after diets rich or poor in vegetables, berries and apple in healthy subjects. Eur J Nutr. 2004;43(3):175–82. https://doi.org/10.1007/s00394-004-0456-4.CrossRefPubMed

83.

Breteler MM. Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging. 2000;21(2):153–60.CrossRefPubMed

84.

Grassi D, Desideri G, Necozione S, Lippi C, Casale R, Properzi G, et al. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J Nutr. 2008;138(9):1671–6.CrossRefPubMed

85.

Balzer J, Rassaf T, Heiss C, Kleinbongard P, Lauer T, Merx M, et al. Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial. J Am Coll Cardiol. 2008;51(22):2141–9. https://doi.org/10.1016/j.jacc.2008.01.059.CrossRefPubMed

86.

Sorond FA, Lipsitz LA, Hollenberg NK, Fisher ND. Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat. 2008;4(2):433–40.PubMedPubMedCentral

87.

Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology. 2013;81(10):904–9. https://doi.org/10.1212/WNL.0b013e3182a351aa.CrossRefPubMedPubMedCentral

88.

Francis ST, Head K, Morris PG, Macdonald IA. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol. 2006;47(Suppl 2):S215–20.CrossRefPubMed

89.

• Lamport DJ, Pal D, Macready AL, Barbosa-Boucas S, Fletcher JM, Williams CM, et al. The effects of flavanone-rich citrus juice on cognitive function and cerebral blood flow: an acute, randomised, placebo-controlled cross-over trial in healthy, young adults. Br J Nutr. 2016;116(12):2160–8. https://doi.org/10.1017/S000711451600430X. This study by Lamport et al. (2016) showed significant increases in inferior and middle right frontal regional perfusion as well as some cognitive enhancement only 2 h following consumption of a high-flavonone drink in healthy young adults, compared to baseline and controls. These findings suggest that a high intake of flavonoids could produce efficient and striking effects on brain vascular function. CrossRefPubMed

90.

Gage FH. Mammalian neural stem cells. Science. 2000;287(5457):1433–8.CrossRefPubMed

91.

Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132(4):645–60. https://doi.org/10.1016/j.cell.2008.01.033.CrossRefPubMed

92.

Hollman PCH. Absorption, bioavailability, and metabolism of flavonoids. Pharm Biol. 2004;42(sup1):74–83. https://doi.org/10.1080/13880200490893492.CrossRef

93.

Xie Y, Yang W, Tang F, Chen X, Ren L. Antibacterial activities of flavonoids: structure-activity relationship and mechanism. Curr Med Chem. 2015;22(1):132–49.CrossRefPubMed

94.

Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry. 2005;66(18):2281–91. https://doi.org/10.1016/j.phytochem.2005.05.022.CrossRefPubMed

95.

Duda-Chodak A. The inhibitory effect of polyphenols on human gut microbiota. J Physiol Pharmacol. 2012;63(5):497–503.PubMed

96.

Nohynek LJ, Alakomi HL, Kahkonen MP, Heinonen M, Helander IM, Oksman-Caldentey KM, et al. Berry phenolics: antimicrobial properties and mechanisms of action against severe human pathogens. Nutr Cancer. 2006;54(1):18–32. https://doi.org/10.1207/s15327914nc5401_4.CrossRefPubMed

97.

Espley RV, Butts CA, Laing WA, Martell S, Smith H, McGhie TK, et al. Dietary flavonoids from modified apple reduce inflammation markers and modulate gut microbiota in mice–3. J Nutr. 2013;144(2):146–54.CrossRefPubMed

98.

Zhang L, Wang Y, Li D, Ho C-T, Li J, Wan X. The absorption, distribution, metabolism and excretion of procyanidins. Food Funct. 2016;7(3):1273–81.CrossRefPubMed

99.

• Krga I, Monfoulet L-E, Konic-Ristic A, Mercier S, Glibetic M, Morand C, et al. Anthocyanins and their gut metabolites reduce the adhesion of monocyte to TNFα-activated endothelial cells at physiologically relevant concentrations. Arch Biochem Biophys. 2016;599:51–9. Krga et al. (2016) demonstrated the ability of anthocyanidin metabolites produced via metabolism by gut microbiota modulated the adhesion of monocytes to human endothelial cells. These findings suggest that flavonoids metabolised by gut microbiota could directly impact the development of atherosclerosis development in its early stages of development. CrossRefPubMed

100.

Verbeek R, van Tol EA, van Noort JM. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol. 2005;70(2):220–8. https://doi.org/10.1016/j.bcp.2005.04.041.CrossRefPubMed

101.

Wang P, Chen H, Zhu Y, McBride J, Fu J, Sang S. Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites–3. J Nutr. 2014;145(2):239–45.CrossRefPubMed

102.

• di Gesso JL, Kerr JS, Zhang Q, Raheem S, Yalamanchili SK, O’hagan D, et al. Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes. Mol Nutr Food Res. 2015;59(6):1143–54. This study by di Gesso et al. (2015) demonstrated that certain combinations of flavonoid metabolites significantly reduced inflammatory cytokine activation beyond their parent flavonoids or their metabolites on their own. These findings suggest that specific combinations of flavonoids could produce optimal anti-inflammatory effects beyond that of their constituents. CrossRefPubMedPubMedCentral

103.

•• Wang D, Ho L, Faith J, Ono K, Janle EM, Lachcik PJ, et al. Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer’s disease beta-amyloid oligomerization. Mol Nutr Food Res. 2015;59(6):1025–40. https://doi.org/10.1002/mnfr.201400544. Wang et al. (2015) demonstrated that metabolites from a high-flavonoid grape seed extract metabolised by gut microbiota significantly interfered with the assembly of neurotoxic Aβ plaques. These findings suggest that gut microbiota could play a key role in modifying the impact of flavonoids on classical AD neuropathology development. CrossRefPubMedPubMedCentral

104.

Prince M, Knapp M, Guerchet M, McCrone P, Prina M, Comas-Herrera A, et al. Dementia UK: update. Alzheimer’s Soc. 2014;

Title: Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration
Authors: Emma Flanagan
Michael Müller
Michael Hornberger
David Vauzour
Publication date: 01-06-2018
Publisher: Springer US
Published in: Current Nutrition Reports / Issue 2/2018
Electronic ISSN: 2161-3311
DOI: https://doi.org/10.1007/s13668-018-0226-1

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