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School of BiosciencesJohn Harwood
Bruce Caterson
Clare Hughes
How may dietary n-3 polyunsaturated fatty acids
alleviate Alzheimer's disease?
Alzheimer’s Research Network - May 23rd 2008
School of Psychology
Mark Good
Cécile Bascoul
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
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.
Methods Experiment on mice WT and Tg2576 (APPsw)
Behavioural changes
Biochemical changes
WTTg WTTg
Normal diet
+ 5% DHA + 5% control oil
Foraging experiment
?
1 error = 1 return
• Males + females• Diets at 4 months• 12 months of age
ALZHEIMER’S MOUSE NORMAL MOUSE
8 min 30s8 errors
1 min 35s1 error
Average mean errors(mean ± SEM)
Foraging experiment
0
2
4
6
8
10
12
14
Tg oil WT oil Tg DHA WT DHA
Ave
rag
e m
ean
err
ors
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)
Main fatty acids in cortex
0%
5%
10%
15%
20%
25%
30%
16:0 18:0 18:1n-9 18:1n-7 20:4n-6 22:4n-6 22:6n-3(DHA)
Fatty acids
Tg oil (n=6)
WT oil (n=6)
Tg DHA (n=6)
WT DHA (n=6)
Main fatty acids: > 2% of total fatty acids
(mean ± SD)
DHA is incorporated in cortex, cerebellum and hippocampus
Individual phospholipids - TLC
1st
2nd
PE
PC
PSSph
DPG
Mouse brain lipids
PI
0%5%
10%15%20%25%30%35%40%45%50%
16:0(palmitic)
18:0(stearic)
18:1n-9 18:1n-7 20:4n-6 (AA) 22:4n-6 22:6n-3(DHA)
Fatty acids
Tg oil (n = 4)
WT oil (n = 4)
Tg DHA (n = 4)
WT DHA (n = 4)
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
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
X 16:0(palmitic)
X X 18:0(stearic)
18:1n-9 20:4n-6(AA)
22:4n-6 22:6n-3(DHA)
Fatty acids
Tg oil (n = 4)
WT oil (n = 4)
Tg DHA (n = 4)
WT DHA (n = 4)
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
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
16:0
a/16
:0
16:0
p/18
:1
16:1
e/18
:1
16:1
a/18
:1
16:0
a/18
:1
18:0
a/16
:0
16:0
p/20
:4
18:1
p/18
:1
18:0
p/18
:1
18:0
p/18
:0
16:0
a/20
:4
18:1
a/18
:1
18:0
a/18
:1
18:0
a/18
:0
16:0
p/22
:6
17:2
/20:
4
16:0
e/22
:6
16:0
p/22
:5
18:0
p/20
:4
16:0
p/22
:4
18:0
e/20
:4
18:1
p/20
:2
18:1
p/20
:1
17:1
/20:
1
18:0
/20:
6
16:0
a/22
:6
16:0
a/22
:5
18:1
a/20
:4
18:0
a/20
:4
18:0
a/20
:3
18:0
a/20
:1
17:2
/22:
6
18:0
a/20
:0
18:0
p/22
:6
18:0
e/22
:6
18:0
p/22
:5
18:0
p/22
:4
18:1
a/22
:6
18:0
a/22
:6
18:0
a/22
:4
Transitions
Tg oil
WT oil
Tg DHA
WT DHA
**
* *
*
* *
*
Mass SpectrometryPE molecular species in cortex
(mean ± SEM)
Mean fold change of expression of IL-6 in female
0123456
cortex hippocampus
Tg oil
Tg DHA
WT oil
WT DHA
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)
Immunohistochemistry: Aβ 1-40 (21 months of age)
Tg DHA 135
Tg oil 189 Tg oil 180
Tg DHA 149
Tg oil 173
Tg DHA 159
Tg oil
Tg DHA
Conclusions
DHA is incorporated in the brain, mainly in PE.
Cognitive improvement with DHA rich diet
may be due to a reduced inflammation.