The effect of diets on neurodegenerative diseases

Transcription

1 The effect of diets on neurodegenerative diseases Results from the FP7 project LIPIDIDIET A Kiliaan Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience Dept Anatomy and dept Cognitive Neuroscience The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/ ) under grant agreement n o Food, Agriculture and Fisheries, and Biotechnology) KBBE : Impact of diet on ageing

2 Impact of diets on ageing and neurodegeneration in mice models Why is the prevalance of Alzheimer lower in Mediterranean countries? Scarmeas et al neurology 2007

3 Maybe because of: Research questions what is the relation between vascular disorders/impaired cerebral bloodflow, and neurodegeneration? And is it possible to influence these processes with diets?

4 Transgenic mouse models on diets APP695swe /PS1 Δ E9 model for AD ApoE4 model for hypercholesterolemia ApoE ko model for atherosclerosis/stroke Control/soy oil diet cholesterol diet fish oil /DHA diets Behaviour and Cognition assessment Learning and memory tests Morris water maze Study design Imaging and Spectroscopy on 7 T system cerebral blood volume metabolite spectrum Pathology Brain pathology; quantification of amyloid deposition inflammatory markers Quantification of synapses, neurogenesis Aβ in vasculature Aβ in hippocampus

5 duration duration (sec) Behaviour; centre sitting explorative, less anxious center duration genotype (WT vs APP) 8 month p = WT APP/PS

6 Behaviour; rearing in center exploration Duration (s) Open Field - Rearing Per group - 8 months of age wt Control (n=15) tg Control (n=10) AD mice on control diet rear significantly less than wild type mice on control diet (p=0.021) * * * min min min

7 Platform crossings Cognition: effects of DHA on spatial memory Platform crossings % of time in NE quadrant Morris water maze probe * 15-month-old mice (13 mo diet) STD DHA Wild type APP/PS1 DHA improves spatial memory after 13 months Probe reverse Morris Water Maze - platform crossings at 6-7 months Control Fortasyn Probe reverse Morris Water Maze - platform crossings Diet effects at 6-7 months # control (n=21) Fortasyn (n=19) Wild type APP/PS Fortasyn: DHA+Uridine-mono-phosphate Choline, phospholipids Anti-oxidants B vitamins improve spatial memory already after 4-5 months supplementation 0-30 sec p=0.07

8 Cerebral Blood Volume Contrast enhanced MRI

9 ΔR2* hippocampus/total rcbv brain Cerebral Blood Volume Before USPIO After USPIO macrovasculature ΔR2* map microvasculature USPIO enhances the tranverse relaxation rate (ΔR2*) The change in ΔR2* is proportional to the rcbv 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 Hippocampus microvasculature p=0.004 p= p=0.012 Wild type APP/PS1 8 months 12 months

10 % delta R2* relative to Std effects of cholesterol and DHA on rcbv 160,0 140,0 120,0 100,0 80,0 Wild type Fortasyn APP/PS1 STD * 15 and 18 mths DHA increases CBV Cholesterol decreases CBV 60,0 40,0 20,0 0,0 Std(wt) Std(tg) TWD(tg) DHA(tg)

11 Magnetic resonance spectroscopy (MRS): Energy metabolism NAA+NAAG/Cre+PCr ratio Neurodegeneration N acetyl aspartate NAA, neuronal marker brain energy states; ATP and glucose NAA+NAAG/Cre+PCr ratio hippocampus Fig 2. 1H MR spectra of the thalamus/hippocampus region of the mouse brain in vivo. Peak assignments: PCr/Cr = total Cr; Gln = glutamine; Glu = glutamate; Ins = myo-inositol; Tau = taurine; Cho = choline ; NAA = N-Acetylasparate. 1,2 0,8 0,4 * wild type APP/PS1 0 8 months 12 months 11

12 effects of DHA on pathology % parenchymal Abeta in GC % vascular Abeta Results: 15-month-old mice (13 mo diet) * STD(tg) TWD(tg) DHA(tg) DHA decreases amyloid deposition in plaques and bloodvessel walls STD(tg) DHA(tg) TWD(tg) 1 * 0 1 Hooijmans et al in Neurobiol Dis 2009

13 effects of cholesterol on pathology 18-month-old mice (15 mo diet) Cholesterol increases plaques in hippocampus

14 In summary Dietary effects: DHA improves cerebral blood volume, cognition, and pathology in AD mice after 1 year supplementation A combination diet (Fortasyn) of DHA plus antioxidants, vitamins phosphatidylcholine and UMP achieves effect already after 4 months supplementation Future research Preventive Aspects of Nutrition while Ageing (PANA) FP7 KBBE - Food, Agriculture and Fisheries, Biotechnology KBBE : Diet and prevention of functional decline of the elderly

15 Acknowledgments Radboud Univ Nijmegen RUNMC Anatomy/CNS Carlijn Hooijmans Jos Dederen Diane Jansen Valerio Zerbi Radiology Arend Heerschap Andor Veltien Danone Research Laus Broersen Univ of Kuopio KU Heiki Tanila Univ of Bonn UKB Dieter Lütjohann Univer of Alabama at Birmingham Thomas van Groen Many many students! EU consortium 7th framework Lipididiet Univ of Saarland USAAR Hartmann/Fassbender Univ of Kuopio KU Tanila Soininen Univ of Szeged USZEG Penke Tel Aviv University UTA Michaelson Göteborgs Universitet GU Skoog/Gustafson Danone Research B.V. Broersen Karolinska Institutet KAU Wahlund Institute of Physiology, ASCR Dolezal VU University Medical VUMC Scheltens University of Bonn UKB Lütjohann

16 Questions??