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![Page 1: School of Biosciences John Harwood Bruce Caterson Clare Hughes How may dietary n-3 polyunsaturated fatty acids alleviate Alzheimer's disease? Alzheimer’s.](https://reader036.fdocuments.net/reader036/viewer/2022081516/551ae4285503466b6a8b5d68/html5/thumbnails/1.jpg)
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
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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
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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.
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Methods Experiment on mice WT and Tg2576 (APPsw)
Behavioural changes
Biochemical changes
WTTg WTTg
Normal diet
+ 5% DHA + 5% control oil
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Foraging experiment
?
1 error = 1 return
• Males + females• Diets at 4 months• 12 months of age
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ALZHEIMER’S MOUSE NORMAL MOUSE
8 min 30s8 errors
1 min 35s1 error
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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)
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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
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Individual phospholipids - TLC
1st
2nd
PE
PC
PSSph
DPG
Mouse brain lipids
PI
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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
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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
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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)
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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)
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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
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Conclusions
DHA is incorporated in the brain, mainly in PE.
Cognitive improvement with DHA rich diet
may be due to a reduced inflammation.