1. School of Biosciences John Harwood Bruce Caterson Clare Hughes How may dietary n-3 polyunsaturated fatty acids alleviate Alzheimer's disease? Alzheimer’s Research Network - May 23 rd 2008 School of Psychology Mark Good Cécile Bascoul

2. 3 2 1 DHA is a polyunsaturated fatty acid (22:6n-3) In rat brain, DHA constitutes > 17% of the total fatty acids (Horrocks and Farooqui, 2004) Source: fatty fish DHA precursors: EPA (20:5n-3) and ALA (18:3n-3) Docosahexaenoic acid (DHA) Constituent of phospholipids of the cells plasma membrane

3. Positive effects of DHA on AD In mouse/rat models:  DHA Aβ in AD mouse model.  DHA impairment of learning and memory in Aβ-infused rats. In human:  DHA in hippocampus of AD patients.  Dietary n-3 fatty acids or fish risk of AD.

4. Methods Experiment on mice WT and Tg2576 (APPsw)  Behavioural changes  Biochemical changes WT Tg WT Tg Normal diet + 5% DHA + 5% control oil

5. Foraging experiment ? 1 error = 1 return Males + females Diets at 4 months 12 months of age

6. ALZHEIMER’S MOUSE NORMAL MOUSE 8 min 30s 8 errors 1 min 35s 1 error

7. Average mean errors (mean ± SEM) ANOVA: Significant progression with sessions (p = 0.003) Significant effect of genotype (p = 0.013) Non-significant effect of diet (p = 0.132) (n = 12)(n = 10)(n = 11)(n = 10)

8. Main fatty acids: > 2% of total fatty acids (mean ± SD) DHA is incorporated in cortex, cerebellum and hippocampus

9. Individual phospholipids - TLC 1st 2nd PE PC PS Sph DPG Mouse brain lipids PI

10. Fatty acids over 2% of the total fatty acids Main fatty acids in cortex phosphatidylinositol (PI) (mean ± SD) sn-1 (16:0) sn-2 (18:0) PI head group

11. Main fatty acids in cortex phosphatidylethanolamine (PE) (mean ± SD) Fatty acids over 2% of the total fatty acids sn-1 (18:0) sn-2 (DHA) PE head group

12. * * ** * * * * Mass Spectrometry PE molecular species in cortex (mean ± SEM)

13. In female, significant effect of genotype (p = 0.02), diet (p = 0.02) and brain area (p = 0.01). In male, non-significant effect of genotype (p = 0.18), diet (p = 0.50) and brain area (p = 0.66). Q-PCR analysis (mean ± SD)

14. Immunohistochemistry: Aβ 1-40 (21 months of age) Tg DHA 135 Tg oil 189Tg oil 180 Tg DHA 149 Tg oil 173 Tg DHA 159 Tg oil Tg DHA

15. Conclusions DHA is incorporated in the brain, mainly in PE. Cognitive improvement with DHA rich diet may be due to a reduced inflammation.