Effect of flavonoids on learning, memory and neurocognitive performance: Relevance and potential implications for Alzheimer's disease pathophysiology

Journal of the Science of Food and Agriculture

Volumn 94, Issue 6, 2014, Pages 1042-1056

  Vauzour, David ^a  

^a UNIVERSITY OF EAST ANGLIA   (United Kingdom)

Author keywords

Alzheimer's disease; Flavonoids; Memory; Signalling pathways

Indexed keywords

FLAVONOID; NEUROPROTECTIVE AGENT; PLANT EXTRACT;

ALZHEIMER DISEASE; ANIMAL; ARTICLE; BRAIN; COGNITION; COGNITIVE DEFECT; DIET; DRUG EFFECT; HUMAN; LEARNING; MEMORY; PATHOPHYSIOLOGY; PHYTOTHERAPY; SIGNALLING PATHWAYS;

ALZHEIMER'S DISEASE; FLAVONOIDS; MEMORY; SIGNALLING PATHWAYS;

ALZHEIMER DISEASE; ANIMALS; BRAIN; COGNITION; COGNITION DISORDERS; DIET; FLAVONOIDS; HUMANS; LEARNING; MEMORY; NEUROPROTECTIVE AGENTS; PHYTOTHERAPY; PLANT EXTRACTS;

EID: 84896366752     PISSN: 00225142     EISSN: 10970010     Source Type: Journal    
DOI: 10.1002/jsfa.6473     Document Type: Article

References (202)

1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W and Ferri CP, The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dementia 9:63-75 (2013).
2. Brookmeyer R, Gray S and Kawas C, Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88:1337-1342 (1998).
3. WHO, WHO & Alzheimer's Disease International, Ed WHO Press, World Health Organization, Geneva, Switzerland (2012).
4. Legos JJ, Tuma RF and Barone FC, Pharmacological interventions for stroke: failures and future. Expert Opin Investig Drugs 11:603-614 (2002).
5. Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB et al., Clinical trials in head injury. J Neurotrauma 19:503-557 (2002).
6. Gu Y, Luchsinger JA, Stern Y and Scarmeas N, Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer's disease. J Alzheimers Dis 22:483-492 (2010).
7. Gu Y, Nieves JW, Stern Y, Luchsinger JA and Scarmeas N, Food combination and Alzheimer disease risk: a protective diet. Arch Neurol 67:699-706 (2010).
8. 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 69:1921-1930 (2007).
9. Loef M and Walach H, Fruit, vegetables and prevention of cognitive decline or dementia: a systematic review of cohort studies. J Nutr Health Aging 16:626-630 (2012).
10. Nooyens AC, Bueno-de-Mesquita HB, van Boxtel MP, van Gelder BM, Verhagen H and Verschuren WM, Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Br J Nutr 106:752-761 (2011).
11. 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 11:677-708 (2011).
12. Letenneur L, Proust-Lima C, Le GA, Dartigues JF and Barberger-Gateau P, Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 165:1364-1371 (2007).
13. Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K et al., Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr 139:120-127 (2009).
14. Vauzour D, Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev 2012:914273 (2012). DOI: 10.1155/2012/914273
15. Crozier A, Jaganath IB and Clifford MN, Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 26:1001-1043 (2009).
16. Manach C, Scalbert A, Morand C, Remesy C and Jimenez L, Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727-747 (2004).
17. Hakkinen SH, Karenlampi SO, Heinonen IM, Mykkanen HM and Torronen AR, Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J Agric Food Chem 47:2274-2279 (1999).
18. Prior RL, Lazarus SA, Cao G, Muccitelli H and Hammerstone JF, Identification of procyanidins and anthocyanins in blueberries and cranberries (Vaccinium spp.) using high-performance liquid chromatography/mass spectrometry. J Agric Food Chem 49:1270-1276 (2001).
19. Williams RJ, Spencer JP and Rice-Evans C, Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36:838-849 (2004).
20. Spencer JP, Flavonoids: modulators of brain function? Br J Nutr 99(E Suppl 1):ES60-77 (2008).
21. Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C and Spencer JP, The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3:115-126 (2008).
22. Spencer JP, Vauzour D and Rendeiro C, Flavonoids and cognition: the molecular mechanisms underlying their behavioural effects. Arch Biochem Biophys 492:1-9 (2009).
23. Nussbaum RL and Ellis CE, Alzheimer's disease and Parkinson's disease. N Engl J Med 348:1356-1364 (2003).
24. Modrick ML, Didion SP, Sigmund CD and Faraci FM, Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol 296:H1914-1919 (2009).
25. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A et al., Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One 4:e5846 (2009).
26. Jellinger KA, Cell death mechanisms in neurodegeneration. J Cell Mol Med 5:1-17 (2001).
27. Ingram DK, Spangler EL, Iijima S, Kuo H, Bresnahan EL, Greig NH et al., New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment. Ann NY Acad Sci 717:16-32 (1994).
28. Shukitt-Hale B, Mouzakis G and Joseph JA, Psychomotor and spatial memory performance in aging male Fischer 344 rats. Exp Gerontol 33:615-624 (1998).
29. Muir JL, Acetylcholine, aging, and Alzheimer's disease. Pharmacol Biochem Behav 56:687-696 (1997).
30. West RL, An application of prefrontal cortex function theory to cognitive aging. Psychol Bull 120:272-292 (1996).
31. Dixon RA, Wahlin A, Maitland SB, Hultsch DF, Hertzog C and Backman L, Episodic memory change in late adulthood: generalizability across samples and performance indices. Mem Cognit 32:768-778 (2004).
32. Siedlecki KL, Salthouse TA and Berish DE, Is there anything special about the aging of source memory? Psychol Aging 20:19-32 (2005).
33. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ et al., Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19:8114-8121 (1999).
34. Spencer JP, The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev 38:1152-1161 (2009).
35. Sofi F, Abbate R, Gensini GF and Casini A, Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 92:1189-1196 (2010).
36. Tangney CC, Kwasny MJ, Li H, Wilson RS, Evans DA and Morris MC, Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population. Am J Clin Nutr 93:601-607 (2011).
37. 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 13years later. J Nutr 142:76-83 (2012).
38. Devore EE, Kang JH, Breteler MM and Grodstein F, Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol 72:135-143 (2012).
39. Kang JH, Ascherio A and Grodstein F, Fruit and vegetable consumption and cognitive decline in aging women. Ann Neurol 57:713-720 (2005).
40. Morris MC, Evans DA, Tangney CC, Bienias JL and Wilson RS, Associations of vegetable and fruit consumption with age-related cognitive change. Neurology 67:1370-1376 (2006).
41. Butchart C, Kyle J, McNeill G, Corley J, Gow AJ, Starr JM et al., Flavonoid intake in relation to cognitive function in later life in the Lothian Birth Cohort 1936. Br J Nutr 106:141-148 (2011).
42. Casadesus G, Shukitt-Hale B, Stellwagen HM, Zhu X, Lee HG, Smith MA and Joseph JA, Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci 7:309-316 (2004).
43. 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 45:295-305 (2008).
44. 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 7:75-83 (2004).
45. Barros D, Amaral OB, Izquierdo I, Geracitano L, do Carmo Bassols Raseira M et al., Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol Biochem Behav 84:229-234 (2006).
46. Ramirez MR, Izquierdo I, do Carmo Bassols Raseira M, Zuanazzi JA, Barros D and Henriques AT, Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res 52:457-462 (2005).
47. 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 (Berl) 223:319-330 (2012).
48. Burke SN and Barnes CA, Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30-40 (2006).
49. Rendeiro C, Vauzour D, Rattray M, Waffo-Teguo P, Merillon JM, Butler LT et al., Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One 8:e63535 (2013).
50. Stangl D and Thuret S, Impact of diet on adult hippocampal neurogenesis. Genes Nutr 4:271-282 (2009).
51. Patel AK, Rogers JT and Huang X, Flavanols, mild cognitive impairment, and Alzheimer's dementia. Int J Clin Exp Med 1:181-191 (2008).
52. Chan YC, Hosoda K, Tsai CJ, Yamamoto S and Wang MF, Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. J Nutr Sci Vitaminol (Tokyo) 52:266-273 (2006).
53. 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 27:5869-5878 (2007).
54. 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/6J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience 159:1208-1215 (2009).
55. Cohen-Salmon C, Venault P, Martin B, Raffalli-Sebille MJ, Barkats M, Clostre F et al., Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J Physiol Paris 91:291-300 (1997).
56. Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA et al., Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehab 81:668-678 (2000).
57. Shif O, Gillette K, Damkaoutis CM, Carrano C, Robbins SJ and Hoffman JR, Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats. Pharmacol Biochem Behav 84:17-25 (2006).
58. Hoffman JR, Donato A and Robbins SJ, Ginkgo biloba promotes short-term retention of spatial memory in rats. Pharmacol Biochem Behav 77:533-539 (2004).
59. Wang Y, Wang L, Wu J and Cai J, The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br J Pharmacol 148:147-153 (2006).
60. Oyama Y, Chikahisa L, Ueha T, Kanemaru K and Noda K, Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res 712:349-352 (1996).
61. Gajewski A, Gingko biloba and memory for a maze. Psychol Rep 84:481-484 (1999).
62. Stoll S, Scheuer K, Pohl O and Muller WE, Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse. Pharmacopsychiatry 29:144-149 (1996).
63. Chopin P and Briley M, Effects of four non-cholinergic cognitive enhancers in comparinson with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacology 106:26-30 (1992).
64. Ramassamy C, Clostre F, Christen Y and Costentin J, Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP. J Pharm Pharmacol 42:785-789 (1990).
65. Watanabe CM, Wolffram S, Ader P, Rimbach G, Packer L, Maguire JJ et al., The in vivo neuromodulatory effects of the herbal medicine Ginkgo biloba. Proc Natl Acad Sci USA 98:6577-6580 (2001).
66. Field DT, Williams CM and Butler LT, Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol Behav 103:255-260 (2011).
67. Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL and Haskell CF, Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol 24:1505-1514 (2010).
68. Camfield DA, Scholey A, Pipingas A, Silberstein R, Kras M, Nolidin K et al., Steady state visually evoked potential (SSVEP) topography changes associated with cocoa flavanol consumption. Physiol Behav 105:948-957 (2012).
69. Crews WD Jr, Harrison DW and Wright JW, A double-blind, placebo-controlled, randomized trial of the effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health: clinical findings from a sample of healthy, cognitively intact older adults. Am J Clin Nutr 87:872-880 (2008).
70. Pase MP, Scholey AB, Pipingas A, Kras M, Nolidin K, Gibbs A et al., Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. J Psychopharmacol 27:451-458 (2013).
71. Mix JA and Crews WD Jr, An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med 6:219-229 (2000).
72. Mix JA and Crews WD Jr, A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol 17:267-277 (2002).
73. Crews WD Jr, Harrison DW, Griffin ML, Addison K, Yount AM, Giovenco MA et al., A double-blinded, placebo-controlled, randomized trial of the neuropsychologic efficacy of cranberry juice in a sample of cognitively intact older adults: pilot study findings. J Altern Complement Med 11:305-309 (2005).
74. Duffy R, Wiseman H and File SE, Improved cognitive function in postmenopausal women after 12weeks of consumption of a soya extract containing isoflavones. Pharmacol Biochem Behav 75:721-729 (2003).
75. Casini ML, Marelli G, Papaleo E, Ferrari A, D'Ambrosio F and Unfer V, Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril 85:972-978 (2006).
76. Henderson VW, St John JA, Hodis HN, Kono N, McCleary CA, Franke AA et al., Long-term soy isoflavone supplementation and cognition in women: a randomized, controlled trial. Neurology 78:1841-1848 (2012).
77. Ho SC, Chan AS, Ho YP, So EK, Sham A, Zee B et al., Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause 14:489-499 (2007).
78. Francis ST, Head K, Morris PG and Macdonald IA, The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol 47(Suppl 2):S215-220 (2006).
79. Hendrickson SJ and Mattes RD, No acute effects of grape juice on appetite, implicit memory and mood. Food Nutr Res 52 (2008). 10.3402/fnr.v52i0.1891
80. Vanata D and Metzger MM, Acute soy isoflavone consumption does not impact visual-spatial or verbal memory among healthy young adults. North Am J Psychol 9:379 (2007).
81. Alzheimer's Association, 2012 Alzheimer's disease facts and figures. Alzheimers Dement 8:131-168 (2012).
82. Walsh DM and Teplow DB, Alzheimer's disease and the amyloid β-protein, in Progress in Molecular Biology and Translational Science, ed. by David BT. Academic Press, New York, pp. 101-124 (2012).
83. 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 7:270-279 (2011).
84. Mitchell AJ and Shiri-Feshki M, Rate of progression of mild cognitive impairment to dementia: meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand 119:252-265 (2009).
85. 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 37:261-277 (2012).
86. Price DL, Tanzi RE, Borchelt DR and Sisodia SS, Alzheimer's disease: genetic studies and transgenic models. Annu Rev Genet 32:461-493 (1998).
87. Jones L, Harold D and Williams J, Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease. Biochim Biophys Acta 1801:754-761 (2010).
88. Nickerson DA, Taylor SL, Fullerton SM, Weiss KM, Clark AG, Stengard JH et al., Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res 10:1532-1545 (2000).
89. Singh PP, Singh M and Mastana SS, APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 33:279-308 (2006).
90. 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 55:1777-1785 (2007).
91. Hayden KM, Zandi PP, West NA, Tschanz JT, Norton MC, Corcoran C et al., Effects of family history and apolipoprotein E epsilon4 status on cognitive decline in the absence of Alzheimer dementia: the Cache County Study. Arch Neurol 66:1378-1383 (2009).
92. 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 6:412-419.
93. 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 261:921-923 (1993).
94. Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P and Dartigues JF, Intake of flavonoids and risk of dementia. Eur J Epidemiol 16:357-363 (2000).
95. Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B and Joseph JA, Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br J Nutr 103:730-734 (2010).
96. 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 58:3996-4000 (2010).
97. 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 60:794-801 (2012).
98. Dai Q, Borenstein AR, Wu Y, Jackson JC and Larson EB, Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med 119:751-759 (2006).
99. Mehlig K, Skoog I, Guo X, Schutze M, Gustafson D, Waern M et al., Alcoholic beverages and incidence of dementia: 34-year follow-up of the prospective population study of women in Goteborg. Am J Epidemiol 167:684-691 (2008).
100. Krikorian R, Boespflug EL, Fleck DE, Stein AL, Wightman JD, Shidler MD et al., Concord grape juice supplementation and neurocognitive function in human aging. J Agric Food Chem 60:5736-5742 (2012).
101. Le Bars PL, Velasco FM, Ferguson JM, Dessain EC, Kieser M and Hoerr R, Influence of the severity of cognitive impairment on the effect of the Ginkgo biloba extract EGb 761 in Alzheimer's disease. Neuropsychobiology 45:19-26 (2002).
102. Walsh DM and Selkoe DJ, A beta oligomers: a decade of discovery. J Neurochem 101:1172-1184 (2007).
103. 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 287:6912-6927 (2012).
104. Williams RJ and Spencer JP, Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med 52:35-45 (2012).
105. Ebrahimi A and Schluesener H, Natural polyphenols against neurodegenerative disorders: potentials and pitfalls. Ageing Res Rev 11:329-345 (2012).
106. Shimmyo Y, Kihara T, Akaike A, Niidome T and Sugimoto H, Flavonols and flavones as BACE-1 inhibitors: structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim Biophys Acta 1780:819-825 (2008).
107. Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH et al., The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 70:603-614 (2001).
108. 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 1214:177-187 (2008).
109. 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 163:741-749 (2009).
110. 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 281:16419-16427 (2006).
111. Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H and Yamada M, 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 (2003).
112. 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 283:32176-32187 (2008).
113. Hirohata M, Hasegawa K, Tsutsumi-Yasuhara S, Ohhashi Y, Ookoshi T, Ono K et al., The anti-amyloidogenic effect is exerted against Alzheimer's beta-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure. Biochemistry 46:1888-1899 (2007).
114. Mandel SA, Amit T, Kalfon L, Reznichenko L, Weinreb O and Youdim MB, Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis 15:211-222 (2008).
115. Amit T, Avramovich-Tirosh Y, Youdim MB and Mandel S, Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. FASEB J 22:1296-1305 (2008).
116. Mandel S, Amit T, Bar-Am O and Youdim MB, Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents. Prog Neurobiol 82:348-360 (2007).
117. 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 15:558-566 (2008).
118. 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 326:739-744 (2008).
119. 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 101:1596-1606 (2007).
120. Vauzour D, VafeiAdou K, Rice-Evans C, Williams RJ and Spencer JP, Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J Neurochem 103:1355-1367 (2007).
121. Halliwell B, Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634-1658 (2006).
122. Pannala AS, Rice-Evans CA, Halliwell B and Singh S, Inhibition of peroxynitrite-mediated tyrosine nitration by catechin polyphenols. Biochem Biophys Res Commun 232:164-168 (1997).
123. Russo A, Acquaviva R, Campisi A, Sorrenti V, Di Giacomo C, Virgata G et al., Bioflavonoids as antiradicals, antioxidants and DNA cleavage protectors. Cell Biol Toxicol 16:91-98 (2000).
124. Visioli F, Bellomo G and Galli C, Free radical-scavenging properties of olive oil polyphenols. Biochem Biophys Res Commun 247:60-64 (1998).
125. Schroeter H, Spencer JP, Rice-Evans C and 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 358:547-557 (2001).
126. Bliss TV and Collingridge GL, A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31-39 (1993).
127. Malenka RC and Bear MF, LTP and LTD: an embarrassment of riches. Neuron 44:5-21 (2004).
128. Alberini CM, Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:121-145 (2009).
129. Bramham CR and Wells DG, Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8:776-789 (2007).
130. Martin KC, Barad M and Kandel ER, Local protein synthesis and its role in synapse-specific plasticity. Curr Opin Neurobiol 10:587-592 (2000).
131. Barco A, Bailey CH and Kandel ER, Common molecular mechanisms in explicit and implicit memory. J Neurochem 97:1520-1533 (2006).
132. Impey S, McCorkle SR, Cha-Molstad H, Dwyer JM, Yochum GS, Boss JM et al., Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119:1041-1054 (2004).
133. Llorens F, Garcia L, Itarte E and Gomez N, Apigenin and LY294002 prolong EGF-stimulated ERK1/2 activation in PC12 cells but are unable to induce full differentiation. FEBS Lett 510:149-153 (2002).
134. Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E and Rice-Evans C, MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23:861-880 (2002).
135. Levites Y, Youdim MB, Maor G and 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 63:21-29 (2002).
136. Impey S, Smith DM, Obrietan K, Donahue R, Wade C and Storm DR, Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1:595-601 (1998).
137. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G and Silva AJ, Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59-68 (1994).
138. Finkbeiner S, CREB couples neurotrophin signals to survival messages. Neuron 25:11-14 (2000).
139. Tully T, Bourtchouladze R, Scott R and Tallman J, Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2:267-277 (2003).
140. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM and Greenberg ME, CREB: a major mediator of neuronal neurotrophin responses. Neuron 19:1031-1047 (1997).
141. Maher P, Akaishi T and Abe K, Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci USA 103:16568-16573 (2006).
142. Wang W, Wang F, Yang YJ, Hu ZL, Long LH, Fu H, Xie N and Chen JG, The flavonoid baicalein promotes NMDA receptor-dependent long-term potentiation and enhances memory. Br J Pharmacol 162:1364-1379 (2011).
143. Vlahos CJ, Matter WF, Hui KY and Brown RF, A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241-5248 (1994).
144. Schratt GM, Nigh EA, Chen WG, Hu L and Greenberg ME, BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24:7366-7377 (2004).
145. Yin Y, Edelman GM and Vanderklish PW, The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci USA 99:2368-2373 (2002).
146. 2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci 21:5484-5493 (2001).
147. Haque AM, Hashimoto M, Katakura M, Tanabe Y, Hara Y and Shido O, Long-term administration of green tea catechins improves spatial cognition learning ability in rats. Journal of Nutrition 136:1043-1047 (2006).
148. Levites Y, Amit T, Youdim MB and Mandel S, Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. J Biol Chem 277:30574-30580 (2002).
149. Ito H, Sun XL, Watanabe M, Okamoto M and Hatano T, Chlorogenic acid and its metabolite m-coumaric acid evoke neurite outgrowth in hippocampal neuronal cells. Biosci Biotechnol Biochem 72:885-888 (2008).
150. Reznichenko L, Amit T, Youdim MB and Mandel S, Green tea polyphenol (-)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93:1157-1167 (2005).
151. Agostinho P, Cunha RA and Oliveira C, Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Curr Pharm Des 16:2766-2778.
152. Pratico D and Trojanowski JQ, Inflammatory hypotheses: novel mechanisms of Alzheimer's neurodegeneration and new therapeutic targets? Neurobiol Aging 21:441-445; discussion 451-443 (2000).
153. 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 101(Suppl 1):S1-45 (2009).
154. 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 30:569-578 (2010).
155. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM et al., Inflammation and Alzheimer's disease. Neurobiol Aging 21:383-421 (2000).
156. Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A and Blennow K, Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull 61:255-260 (2003).
157. 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 12:151-156 (2007).
158. 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 5:398-405 (2009).
159. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC et al., Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study. Arch Neurol 61:668-672 (2004).
160. Kravitz BA, Corrada MM and Kawas CH, Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old. Alzheimers Dement 5:318-323 (2009).
161. Duong T, Nikolaeva M and Acton PJ, C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease. Brain Res 749:152-156 (1997).
162. 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 629:245-252 (1993).
163. Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M et al., Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 74:1022-1029 (2010).
164. Williams P, Sorribas A and Howes MJ, Natural products as a source of Alzheimer's drug leads. Nat Prod Rep 28:48-77 (2011).
165. 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 23:159-169 (2004).
166. González-Gallego J, García-Mediavilla MV, Sánchez-Campos S and Tuñón MJ, Fruit polyphenols, immunity and inflammation. Br J Nutr 104:S15-S27 (2010).
167. Spencer JP, Vafeiadou K, Williams RJ and Vauzour D, Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Aspects Med 33:83-97 (2012).
168. Kao TK, Ou YC, Raung SL, Lai CY, Liao SL and Chen CJ, Inhibition of nitric oxide production by quercetin in endotoxin/cytokine-stimulated microglia. Life Sci 86:315-321 (2010).
169. Chen JC, Ho FM, Pei-Dawn Lee C, Chen CP, Jeng KC, Hsu HB et al., Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. Eur J Pharmacol 521:9-20 (2005).
170. Sharma V, Mishra M, Ghosh S, Tewari R, Basu A, Seth P et al., Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 73:55-63 (2007).
171. Bureau G, Longpre F and Martinoli MG, Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. J Neurosci Res 86:403-410 (2008).
172. Manach C, Williamson G, Morand C, Scalbert A and Remesy C, Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81:230S-242S (2005).
173. Vafeiadou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ and Spencer JP, The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys 484:100-109 (2009).
174. Zhang F, Qian L, Flood PM, Shi JS, Hong JS and Gao HM, Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity. J Pharmacol Exp Ther 333:822-833 (2010).
175. Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF and Lin JK, Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 20:1945-1952 (1999).
176. Huang Q, Wu LJ, Tashiro S, Gao HY, Onodera S and Ikejima T, (+)-Catechin, an ingredient of green tea, protects murine microglia from oxidative stress-induced DNA damage and cell cycle arrest. J Pharmacol Sci 98:16-24 (2005).
177. Kim H, Kim YS, Kim SY and Suk K, The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci Lett 309:67-71 (2001).
178. Dell'Albani P, Santangelo R, Torrisi L, Nicoletti VG, de Vellis J and Giuffrida Stella AM, JAK/STAT signaling pathway mediates cytokine-induced iNOS expression in primary astroglial cell cultures. J Neurosci Res 65:417-424 (2001).
179. Suk K, Lee H, Kang SS, Cho GJ and Choi WS, Flavonoid baicalein attenuates activation-induced cell death of brain microglia. J Pharmacol Exp Ther 305:638-645 (2003).
180. Spilsbury A, Vauzour D, Spencer JP and Rattray M, Regulation of NF-kappaB activity in astrocytes: effects of flavonoids at dietary-relevant concentrations. Biochem Biophys Res Commun 418:578-583 (2012).
181. Nanri A, Yoshida D, Yamaji T, Mizoue T, Takayanagi R and Kono S, Dietary patterns and C-reactive protein in Japanese men and women. Am J Clin Nutr 87:1488-1496 (2008).
182. Salas-Salvado J, Garcia-Arellano A, Estruch R, Marquez-Sandoval F, Corella D, Fiol M et al., Components of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease. Eur J Clin Nutr 62:651-659 (2008).
183. Chun OK, Chung SJ, Claycombe KJ and Song WO, Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr 138:753-760 (2008).
184. 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 137:1951-1954 (2007).
185. 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 38:499-506 (2005).
186. Freese R, Vaarala O, Turpeinen AM and 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 43:175-182 (2004).
187. Boots AW, Wilms LC, Swennen EL, Kleinjans JC, Bast A and Haenen GR, In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers. Nutrition 24:703-710 (2008).
188. Breteler MM, Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging 21:153-160 (2000).
189. Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA et al., Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 88:38-50 (2008).
190. Kay CD, Hooper L, Kroon PA, Rimm EB and Cassidy A, Relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomised controlled trials of flavonoid-rich food products. Mol Nutr Food Res 56:1605-1616 (2012).
191. Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK et al., (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 103:1024-1029 (2006).
192. Heiss C, Dejam A, Kleinbongard P, Schewe T, Sies H and Kelm M, Vascular effects of cocoa rich in flavan-3-ols. JAMA 290:1030-1031 (2003).
193. Heiss C, Finis D, Kleinbongard P, Hoffmann A, Rassaf T, Kelm M et al., Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1week. J Cardiovasc Pharmacol 49:74-80 (2007).
194. 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 15days of consuming high-polyphenol dark chocolate. J Nutr 138:1671-1676 (2008).
195. McCullough ML, Chevaux K, Jackson L, Preston M, Martinez G, Schmitz HH et al., Hypertension, the Kuna, and the epidemiology of flavanols. J Cardiovasc Pharmacol 47(Suppl 2):S103-109; discussion 119-121 (2006).
196. 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 51:2141-2149 (2008).
197. Hollenbecrg NK, Martinez G, McCullough M, Meinking T, Passan D, Preston M et al., Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension 29:171-176 (1997).
198. Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG et al., Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433-445 (1995).
199. Sorond FA, Lipsitz LA, Hollenberg NK and Fisher ND, Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat 4:433-440 (2008).
200. Gage FH, Mammalian neural stem cells. Science 287:1433-1438 (2000).
201. Zhao C, Deng W and Gage FH, Mechanisms and functional implications of adult neurogenesis. Cell 132:645-660 (2008).
202. Palmer TD, Willhoite AR and Gage FH, Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479-494 (2000).