ILSI Europe Satellite Workshop on Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet July 2014, Milan, Italy

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1 ILSI Europe Satellite Workshop on Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet July 2014, Milan, Italy Flavonoids as modulators of APP Processing: A Dietary intervention for Dementia? Dr Robert Williams University of Bath, UK Organised by The ILSI Europe Nutrition and Mental Performance Task Force

2 Flavonoids as modulators of APP Processing: A Dietary intervention for Dementia? Dr Robert Williams University of Bath, UK

3 Preserving Synaptic Function in Dementia 3

Alzheimer s Disease Leading cause of dementia Projected rise from 44 million (2013) to

of cases sporadic, age of onset >65 years Risk Factors: Genome wide association

onset 25 61 years Rare autosomal dominant inherited mutations: Amyloid precursor

4 Alzheimer s Disease Leading cause of dementia Projected rise from 44 million (2013) to 135 million affected individuals by 2050 *Source Alzheimer s Disease International 98% of cases sporadic, age of onset >65 years Risk Factors: Genome wide association studies: clusterin, PICALM, TREM2 ApoE4 Allele: one copy increases risk x 4 1-2% early onset years Rare autosomal dominant inherited mutations: Amyloid precursor protein (APP) Presenilin 1 and 2 (PS1, PS2) Trisomy 21 Downs patients present with AD pathology ~ age 40 4

5 Areas for dietary intervention in AD? Targets for Slowing Onset & Reducing Dementia risk? Targets for Neuroprotection Targets for Symptoms & Palliative Care 5

6 Amyloid Precursor Protein (APP) Processing Amyloid β plaque formation 6

7 Screening platform for APP processing Cortical Neurons APP-GAL4 / GFP 7 Hoey, Williams, Perkinton (2009) J. Neuroscience

8 Assay reports β -secretase processing Cox, Choudhry, Peacey, Perkinton, Richardson, Howlett, Lichtenthaler, Francis, Williams (2014) under review 8

g. berry fruit Catechin Epicatechin Epigallocatechin

9 Screening Flavonoids Flavanols e.g. tea, wine Flavanones e.g. citrus Flavonols e.g. fruit, veg Isoflavones e.g. soy Anthocyanins e.g. berry fruit Catechin Epicatechin Epigallocatechin Epicatechin Gallate Epigallocatechin Gallate 9

10 Flavonoid (nm) inhibition of APP processing % Activity Compared to Control EC 50 = 22 nm (6 h) Flavonoid group Compound name 100 nm Flavonol Fisetin ±11.7 Kaempferol 103±54.1 Kaempferol 3O Rutinoside 83.0±44.7 Quercetin 98.6±18.1 Flavone Apigenin 90.9±27.9 Apigenin 7O Glucoside 102±13.6 Coumarin 137±15.1 Diosmetin 90.4±14.3 Hyperoside 94.1±14.3 Sinensetin ±26.1* Flavanone Hesperetin 134±14.5 EC 50 = 14 nm (24 h) Narirutin 126±20.7 Anthocyanin Cyanidin Chloride 111±39.8 Delphinidin Chloride 114±32.9 Pelargonidin Chloride ±6.23 Flavanol (+) Catechin 97.6±14.7 (-) Epicatechin 107±35.1 Epicatechin Gallate 115±28.1 Epigallocatechin ±23.3* Epigallocatechin Gallate 91.9±33.6 Cox, Choudhry, Peacey, Perkinton, Richardson, Howlett, Lichtenthaler, Francis, Williams (2014) under review 10

ADAM10 levels 11 Cox, Choudhry, Peacey, Perkinton, Richardson,

11 No evidence that (-) Epicatechin enhances nonamyloidogenic APP processing No change in α-ctfs No change in sappα No change in ADAM10 levels 11 Cox, Choudhry, Peacey, Perkinton, Richardson, Howlett, Lichtenthaler, Francis, Williams (2014) under review

12 (-) Epicatechin as a non-catalytic inhibitor of BACE activity? Reduced β-ctfs in cortical neurons Inhibition of BACE activity in EC treated cell lysates but not in cell free assays No change in BACE1 levels Reduced Aβ secretion in APP/PS1 cultured neurons Cox, Choudhry, Peacey, Perkinton, Richardson, Howlett, Lichtenthaler, Francis, Williams (2014) under review 12

21 days Control Epicatechin Cox, Choudhry, Peacey, Perkinton,

13 (-) Epicatechin reduces Amyloid β pathology in APP/PS1 transgenic mice TASTPM (7 m) ~15 mg/day in drinking water for 21 days Control Epicatechin Cox, Choudhry, Peacey, Perkinton, Richardson, Howlett, Lichtenthaler, Francis, Williams (2014) under review 13

14 Flavonoids: mechanisms of action in AD 14

15 Mechanisms beyond APP: Tau? Williams RJ and Spencer JPE (2012) Free Radical Biology and Medicine 52,

16 Dietary Flavonoids: Challenges & Future Directions Mechanisms underpinning activity, Bioavailability, metabolism and pharmacokinetics Proof of efficacy in humans, need for biomarkers 16

Acknowledgements Williams Lab: University of Bath Dr Carla Cox

Student (BBSRC) Dr Bernard Law Postdoctoral Research Assistant

Professor Roy Jones, RICE, RUH, Bath Professor Paul Francis, Brains

GlaxoSmithKline APP/PS1 mice Dr Michael Perkinton Medimmune-AZ -

Julien Licchesi University of Bath - Proteostasis Prof Will Wood

17 Acknowledgements Williams Lab: University of Bath Dr Carla Cox former PhD Student (MRC & Alzheimer s Society) Tori Hammond - PhD Student (BBSRC) Dr Bernard Law Postdoctoral Research Assistant Biomarker Discovery: Dr Jean Van den Elsen, University of Bath Professor Roy Jones, RICE, RUH, Bath Professor Paul Francis, Brains for Dementia Research, Collaborators: Dr Jill Richardson GlaxoSmithKline APP/PS1 mice Dr Michael Perkinton Medimmune-AZ - GAL4 assay Dr Stefan Litchenthaler DZNE, Munich - APP processing Dr Julien Licchesi University of Bath - Proteostasis Prof Will Wood University of Bristol Innate Immunity Prof Jeremy Spencer University of Reading - Flavonoids 17

The Bioavailability of Dietary Flavonoids & Related Phenolic Compounds. Dietary phenolics. Feeding Studies. Stomach. Tissues. bile.

The Bioavailability of Dietary Flavonoids & Related Phenolic Compounds Dietary phenolics Stomach Tissues Possible Routes for Consumed Dietary Phenolics in Humans bile General circulation Small intestine