Plant Bioactives, inflammation and ageing. Dr. David Vauzour Norwich Medical School

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1 Plant Bioactives, inflammation and ageing Dr. David Vauzour Norwich Medical School

2 Ageing population Ageing brains Over 35 million people live with dementia worldwide today and this number is projected to increase to 115 million by 2050 (World Alzheimer report 2010) Global population of people over age 65 has risen dramatically from 150 million in 1960 to over 500 million in 2010 (WDI, world bank, 2011) Accelerated rate of worldwide dementia carry significant health care, social and public policy implications

3 Ageing brains Forgetful brains Changes at molecular and morphological levels Evidence of the aging process at different levels hippocampus Memory and learning impairments Age-related cognitive decline and other neurological disorders (e.g Alzheimer Disease) strongly associated with Learning and Memory Impairments

4 Ageing & Disease: The two evil twins Inflammation Increase in NO production Increase in TNF-α, IL-1β, CRP APOε4 genotype Neurotoxicity Oxidative stress DNA damage, protein aggregation Neurotoxins ( Aβ)

5 Inflammation: the secret killer Gorman, C., Park, A., & Dell, K. (2004, February 23). The fires within. Time, 1-8.

6 Inflammaging as a prodrome to AD Inflammaging = ageing is accompanied by low grade chronic inflammation Inflammaging may remain subclinical in many elderly individuals A portion of individual ( high responder inflammatory genotype) may shift to number of age-associated diseases

7 Evidence that inflammation is centrally involved in the pathology of AD In AD brain activated glial cells surround amyloid-β plaques (Aβ or senile plaque), one of the defining pathological features of AD) In AD brains cytokines Gene variants in cytokines & receptor shown to modulate AD risk NSAID shown to lower AD risk

8 Nonsteroidal anti-inflammatory drugs There is an inflammatory component in AD Large studies have shown that some non steroid antiinflammatory drugs (NSAIDs) decrease the incidence of AD The mechanism behind this effect is unknown, but might be due to lower levels of Aβ-42 Ibuprofen-treated APP mice show reduced Aβ-42 in brain S. WEGGEN et al. Nature 414, (2001) Clinical trials ongoing

9 Complex/mg protein IL-1b levels (pg/mg) E3FAD E4FAD Ab42 (ng/mg tissue) Extracellular Aβ, APOE and inflammation A. Extracellular Ab, E4FAD > E3FAD B. Total Ab42 levels E4FAD>E3FAD 2-months 4-months 6-months Sub CA1 Cortex CA * C. Ab induced astrocyte activation Ab (MOAB-2) GFAP ApoE Merge D. ApoE/Ab complex: E4FAD<E3FAD Hippo * E. IL-1b: E4FAD>E3FAD 1 * Youmans et al J Biol Chem (50): ; Tai et al. J Biol Chem (8):

10 Neuroinflammation and cognitive performances Increased neuroinflammation can perturb the proper function of brain neurons by: Impeding the efficiency of LTP required for new memory formation Amplify the production and potentiate the effects of the Aβ protein that is key driver of neuronal dysfunction and death in AD Increase the level of acetyl cholinesterase (AChE) activity and promote free radical generation which can also contribute to the pathology observed in AD

11 20% & 33% lifetime risk of dementia in men and women Inflammation APOE genotype Diet A delay onset 5y = decline in prevalence by half A delay onset 1y = decline in prevalence by 5% (Brookmeyer et al., 1998)

12 A diverse array of brain bioactives Omega-3 (Fish, flaxseed) Flavonoids (Fruits, Veg) Curcumin (Turmeric) B Vitamins - Folic acid (Vit B9) - Cyanocobalamin (Vit B12) - Pyridoxine (Vit B6)

13 Flavonoids : Sources Fruit and vegetables: (All classes) Tea: (Flavanols) Citrus: (Flavanone) Red wine: (Flavanol, Flavonols) Cocoa: (Flavanols and procyanidins) Berries: (Anthocyanins) 13

14 The action of Flavonoids in our body Del Rio et al. Antioxidant & Redox Signaling, 2012

15 Epidemiological Studies Age-Related Dementia Study Age range Dietary Factor Outcome Bordeaux Study 65 and over Wine Reduced Canadian Study 65 and over Wine Coffee Reduced Reduced Nurse s Health Study 70 and over Fruit Vegetables Reduced Reduced Chicago Study 65 and over Vegetables Fruits Reduced NC PAQUID Study 65 and over Flavonoids Reduced Kame Study Honolulu-Asia Aging Study 65 and over 65 and over Fruit juices Vit C, E β-carotene Tea Flavonoids Reduced NC NC NC NC

16 Epidemiology Human Trials Plant bioactives and inflammation: epidemiology and intervention studies Product Age range Dosage/duration Outcome Fruit and vegetables Adults Dietary intake Reduced CRP Fruit and vegetables 13-17y Dietary intake Reduced CRP, IL6 Food rich in antiox 70 and over Dietary intake Reduced CRP, IL6 ACN from BB Black tea Cherries Black tea Berries and apple Pomegranate 40-74y 300mg/d/3w Reduced IL4, IL8, IL13 and IFN-g 18-55y 6 weeks Reduced CRP 18-55y 280g/d/28d Reduced CRP, NO ~54y 900ml/d/4w = CRP and 8-OHdG 17-52y 6 weeks = CRP and ICAM y 800mg = IL-6

17 Fruits and Vegetables Greater frequency of fruit and vegetable intake was associated with lower CRP concentrations. Antioxidant components of fruits and vegetables may contribute to their anti-inflammatory effect. Berries, spices Pigments in brightly colored fruits, vegetables and berries contain many phytochemicals that have anti-inflammatory properties. Results are however inconsistent and further RCTs are necessary Giugliano, D., Ceriello, A., & Esposito, K. (2006). The effects of diet on inflammation. Journal of the American College of Cardiology, 48(4),

18 Do flavonoids cross BBB? Flavonoids intravenous administration: - Naringenin and naringenin glucuronide presence into rat cerebral cortex (20mg/kg) (Peng et al J Chromatogr B Biomed Sci Appl 714(2):369-74) - Hesperetin detected in rat brain (50 mg/ml) (Tsai & Chen 2000 J Food Drug Anal 8:331-36) Flavonoids oral administration: - Tea epigallocatechin gallate detection in mouse brain (Suganuma et al. Carcinogenesis (10):1771-6) - Epicatechin glucuronide and 3-O-methylated epicatechin glucuronide detected in rat brain tissue (100 mg/kg body w/day) (Abd El Mohsen et al Free Radic Biol Med 3(12): ) - Pelargonidin detection in rat brains (Abd El Mohsen et al Br J Nutr 95(1):51-8.

19 Concentration (nmol/g of tissue) Brain level of Flavonoids Hippocampus Cortex Anthocyanins Flavanols Methylated flavanols Williams et al Free Radic Biol Med Aug 1;45(3):

20 Other mechanism of Bioactivity Extracellular Neurotoxins (CysDA, DHBT1, Aβ) Oxidative stress, APOε4 Cytoplasm p38 Oxidative and Metabolic stress Akt IL-1β, TNF-α inos, COX-2 ERK JNK Flavonoids / Metabolites FoxO NF-κB PKC Nrf2 Keap1 CREB P300-CBP FoxO Nrf2 Promoter ARE PDE4 AOE, Bcl-2, BDNF AOE, Ph 2 enz Nucleus SIRT 1 Vauzour D. 2012, Oxid Med Cell Longev. 2012:

21 TNF alpha (mg/ml) Lipid Concentration Impact of diet on neuroinflammation Placebo BB Flavonoids 6 5 Placebo EPA/DHA Decrease in saturated FA Increase in PUFAs * ** Placebo Treatment 0 Hippocampus Cortex Remainder

22 Signalling in Neuroinflammation/Neurotoxicity Activation Inhibition ROS/RNS DHBT-1 CysDA Inhibition by Flavonoids Microglia/Astrocyte inos NO STAT-1 TNF-a p38 ASK1 JNK1/2 BAD Bcl-xL Caspase-8 Scavenging by Flavonoids Activation by Flavonoids Akt ERK1/2 Caspase-9 Caspase-3 CREB PI3K MEK1/2 IFN CD23 IL-1b TNF-a Neuronal apoptosis Neuron Vauzour D, Ravaioli G, Vafeiadou K et al. Arch Biochem Biophys. 2008;15;476(2): Vauzour D, Vafeiadou K, Rice-Evans C et al. J Neurochem. 2007; 103(4): Vafeiadou K, Vauzour D, Hung Yi Lee et al. Arch Biochem Biophys. 2009; 484;

23 Curcumin affect amyloid in vivo Curcumin crosses the BBB and binds to plaques Yang, et al. J. Biol. Chem. (2005);280:

24 Curcumin suppresses amyloid accumulation in aged APP transgenic mice Tg2576 mice were placed on chow supplemented w. curcumin at 17 months of age and brains were removed after 22 months A-C = control D-F = Curcumin G. Image analysis of plaque burden H. ELISA measurement of guanidine- soluble Aβ Yang, F. et al. J. Biol. Chem. 2005;280:

25 Complementary effects of plant bioactives APP DHA APP Bioactives β-secretase (BACE) F4-isoprostanes PLA2 α-secretase (ADAM) Bioactives -secretase (Presenilin1&2) Oxidative stress LOX2 SAPPα (612) amino acids) Aβ40 & Aβ42 NFκB AP-1, HIF-1, STAT1 NPD1 Neuronal survival clearance ε3 >>> ε4 APOε ε4 >>> ε3 Inflammatory gene expression Bad, Bax, Bid, Bik Bcl-2, Bcl-xL, Bfl-1(A1) Caspase-3 Bioactives Neuronal apoptosis Vauzour D and Minihane AM, Nutrition & Aging (2012) 1, 41-53

26 Summary - Chronic and systemic pro-inflammatory state are critical perpetrators of aging and age related diseases, leading to an accumulation of subtle tissue damages (i.e brain) - Inflammatory response is evidenced by increased serum levels of pro-inflammatory cytokines and reactive oxygen species - Plant bioactives may be capable of influencing the immune-tobrain signaling pathways, thus limitating neuronal injury - Links between plant bioactives and inflammatory regulation are worthy of further investigation and more epidemiological studies and prospective randomized trials in clinical conditions are required

27 Acknowledgements Nutritional Sciences Pr. Jeremy Spencer Dr. Manal Abd El Mohsen Dr. Giulia Corona Dr. Catarina Rendeiro Dr. Ana Rodriguez-Mateos GESVAB Pr. Jean Michel Mérillon Dr. Pierre Waffo-Téguo Dr Tristan Richard Psychology Dr. Laurie Butler Dr. Claire Williams