Transcript Nutritional properties of Meat

REGIONAL SYMPOSIUM ON
ALZHEIMER’S DISEASE AND RELATED DISORDERS
IN THE MIDDLE EAST
Istanbul, Turkey
October 1-2, 2005
Convener: Robert P. Friedland, MD
LOC Chair: Murat Emre, MD
Gene environment interactions
in Alzheimer’s Disease
Robert P. Friedland, Lindsay A. Farrer, Rivka
Inzelberg, Amin Abuful, Magda Marsarwa, Rosa
Strugatsky, Clinton Baldwin, Grace Petot
Cleveland, Ohio, USA; Boston, Massachussetts
USA; Hadera, Israel
CWRU
Lab.Neurogeriatrics
S. Debanne, PhD
R. Friedland, MD
T. Fritsch, PhD
E. Grady, BA
K. Gustaw, MD, PhD
S. Humphrey, BA
A. Lerner, MD
G. Petot, MS
CWRU
Dept. Pathology
G. Perry, PhD
M. Smith, PhD
Boston Univ.
C. Baldwin, PhD
L. Farrer, PhD
Sun Health Res. Inst.
L. Sparks, PhD
Cleveland Clinic
D.Jacobsen,PhD
Hillel Yaffe Med.
Center/Technion
A. Abuful, RN
R. Inzelberg, MD
M. Masarwa, MD
R. Stugatsky
Hadassah Hosp
Hebrew
Univ, Jerusalem
I. Biran, MD
J. Kark, MD, PhD
Y. Newman, PhD
State University of New York,
Stony Brook
D. Goldgaber, PhD
Interactions in Alzheimer’s
disease
• What’s going wrong in the AD brain?
• Genes
• Environment
Africans, African Americans
Caucasians
Middle East
• Implications for health and public
policy
Amyloid and aging vessels
• All people over 60 have aortic amyloid
• Medin: an integral fragment of aortic smooth
muscle cell-produced lactadherin
• Also found in temporal arteries
• Comes from smooth muscle cells
Haggqvist et al, 1999; Peng et al, 2002
Amyloid deposited on internal elastic lamina in a
temporal artery without inflammation.
a-secretase----
Helmuth, 2002
a secretase ----
Alzheimer physiology –
choose your poison!
1. APP expression
2. APP cleavage
3. ABeta aggregation and toxicity
4. ABeta clearance from brain to blood
5. ABeta clearance from blood
Why is this important?
Age and Alzheimer’s disease
• The risk of getting the disease doubles
every 5 years after the age of 65
• The most important risk factor for AD is
age
The second most important risk
factor for AD is genetics
Autosomal dominant
chromosome 21
APP
chromosome 14
Presenilin 1
chromosome 1
Presenilin 2
~total > 160 rare but highly penetrant mutations~
Co-dominant
chromosome 19
Apolipoprotein E
Recessive
none ?????????????????????????
What determines the function of
a gene?
1.
2.
3.
4.
5.
Nucleotide sequence
DNA repair
Expression accuracy
Expression levels
Interaction of gene products and
environmental factors
What determines the function of
a gene?
1.
2.
3.
4.
Nucleotide sequence
DNA repair
Expression accuracy
Expression levels – influenced by
both genes and environment!
5. Interaction of gene products and
environmental factors
TTR binds best to
AB 42 (Tsuzuki et al
2000)
TTR and Alzheimer’s disease
•
•
MIRAGE database (L. Farrer, PI)
256 Caucasian AD cases , 306 non-demented sibs,
227 African American AD cases, 165 non-demented
sibs.
•
119 (Caucasian) and 79 (African American) AD
cases and non-demented spouses.
SNP associations were evaluated using familybased association tests, generalized estimating
equations and chi square tests of proportion.
•
No relationships between disease and 3 TTR
polymorphisms were uncovered thus far.
Farrer et al (preliminary data - unpublished)
Chromosome 18
27424463
intron
rs723744
27425782
intron
rs1080094
27428958
intron
rs3794884
TTR and AD
• TTR levels decreased in plasma and CSF in
AD patients, cor. with dementia severity
Riiosen et al, 1988; Davidsson et al,1997; Serot et
al,1997; Merched et al, 1998, Riisoen,1988
• In early life AD Tg mice have increased TTR
expression (before ABeta deposition and
neuronal loss)….also neutralization of TTR
enhances AD pathology in AD Tg mice
Stein and Johnson, 2002; Stein et al, 2004
Worldwide distribution of AD
• Age-related
• Less in Asia, Africa, India
• More in African-Americans and
Hispanics than Caucasians or
Africans
• Few studies in the Middle East
Wadı Ara studıes
• Rıvka Inzelberg, Co-Prıncıpal
Investıgator
• Populatıon based survey of genetıc and
envıronmental factors
• Genes: inbreedıng, populatıon bottleneck
• Envıronment: educatıon, smokıng, diet,
actıvıtıes, alcohol, hypertensıon
Every
hereditary
monarch in
Europe at the
beginning of
the 20th
century was a
descendent of
Edward III
(Manrubia et al,
2003)
Edward III, 1312-1377
Alzheimer’s disease in Wadi Ara
• familial clustering of AD [with low Apo
E e4 allele frequency, ~4%], perhaps
related in inbreeding
• genetic linkages of AD to sites on
chromosomes 9, 10 and 12.
• Environmental factors may include low
levels of education and fish
consumption, smoking, high fat diet,
hypertension and physical inactivity.
Alzheimer’s disease in
Africans and African
Americans
• Higher e4 freq. in Africans and African Americans
• Lower AD prevalence and incidence in
Africans and higher in AfricanAmericans (compared to Caucasians)
(Hendrie et al, 1999, Kalaria et al, 1999, Evans
et al, 2000)
Obesity and Alzheimer’s disease
96 cases, 275 Controls; adjusted for year of birth, Apo E genotype,
gender and education. [Petot et al, unpublished]
Dietary fat and AD
• High fat diets during the 40-59 year age period were
not a risk factor for AD, regardless of ApoE status,
and they may be protective.
•
ApoE e4 risk for AD increased 2.7 times with high
linoleic acid diets during the 40-59 year age period.
117 Cases 356 controls, adjusting for year
of birth, Apo E genotype, gender and
education
Petot et al, (ANA, Sept. 2005)
Fish, PUFA and AD
• Fish consumption is linked to lower AD
risk (also CAD, stroke, cancer)
(Kalmijn et al, 2000; Morris et al, 2003, Friedland, 2003)
• Dietary intake of omega 3 PUFAs
influences the expression levels of
many genes controlling resistance to
endogenous free radicals and ABeta
protein balance
Gene expression changes
induced by PUFAs
increased
* TTR
antioxidants
gelsolin
anti-inflamm.
pro-apoptotic casp.
decreased
lipogenesis
ROS
COX2
iNOS
*Short-term administration of omega 3 fatty acids from fish oil
increased TTR transcription 10X in aged rat hippocampus
Puskas LG et al, 2003 Akba et al, 2002,Takahashi et al, 2003,
Lapillonne et al, 2004
Proposal:
- Brain disease with aging are due to the
failure of protective mechanisms
resulting from gene-environment
interactions, including environmental
effects on gene expression
Potentially modifiable
protective factors for AD
• high education and occupational
achievement
• vigorous participation in mental and
physical activities
• no cardiac disease, diabetes,
hypertension
Protective Factors for
Alzheimer’s disease (cont).
• dietary use of antioxidants
• low level of alcohol consumption
• avoidance of obesity, high fat diet and
head injury
Implications for public policy
• Lıfelong educatıon and
opportunıtıes for mental and
physıcal actıvıtıes
• Access to care
• Research fundıng
ACKNOWLEDGEMENTS
• National Institute on
Aging
• Joseph and Florence
Mandel Research Fund
• Nickman Family
• Philip Morris, USA
• Fullerton Family
• GOJO Corp.
• Pfizer, Inc.
• Institute for the Study
of Aging
Peter B. Lewis Building, CWRU
Nutritional properties of Meat
Africa
Fat
(g/100g)
Commercial
Meat
Fat
(g/100g)
• Wildebeast
4.9
• Lamb
21.6
• Waterbuck
1.8
• Pork
22.6
• Cape buffalo
6.3
• Choice beef
23.8
• Eland
4.8
• Extra lean
ground beef
17.1
(adapted from Eaton, 1992)
Enhanced longevity
• “In Western Europe… from 1950 to
2000 the probability of surviving from
age 80 to 100 increased 20-fold.”
(Vaupel et al, Science, 2003)
EURODEM prevalence rates
Male
Female
30-59
0.2%
0.1%
60-64
1.6%
0.5%
65-69
2.2%
1.1%
70-74
4.6%
3.9%
75-79
5.0%
6.7%
80-84
12.1%
13.5%
85-89
18.5%
22.8%
90-94
32.1%
32.3%
95-99
31.6%
36.0%
Age group
O2 Radical Absorbance Capacity
Fresh Fruit
Veggies and Legumes
Blueberries
2,400
Kale
1,770
Blackberries
2,036
Spinach
1,260
Cranberries
1,750
Brussel sp.
980
Strawberries
1,540
Alfalfa sp.
930
Raspberries
1,220
Broccoli
890
Plums
949
Beets
840
Avocado
782
Red Bell P.
460
Oranges
750
Kidney B.
460
Red Grapes
739
Onions
450
Cherries
670
Corn
402
Aging and dementia in the
Middle East
• 22 countries
• Over 300 million people
MMWR Weekly, Volume 54, No. 8, March 4, 2005
90
80
70
60
50
40
30
20
10
0
% with e4
% with no
e4
Percent of obese cases & controls
Percent normal cases & controls
Obesity and Apo E genotype
90
80
70
60
50
% with e4
40
% with no e4
30
20
10
0
Cases
Controls
n=53
n=160
Cases
n=13
Controls
n=17
Odds Ratio with Confidence Intervals
Odds ratios for Alzheimer's disease adjusted for year
of birth, education and APOEe4
20
17.62
15
18.08
16.06
10
8.07
5
0
4.34
4.62
1.18
1.21
Obese vs Normal
Obese vs
Overw eight
3.6
With APOE e4
100
80
Percent with APOE e4
72%
60
54%
40
18%
20
19%
0
Obese
cases
n=13
Obese
controls
n=17
Non-obese Non-obese
cases
controls
n=83
n=258
Other influences on TTR
• TTR is also increased by Ginkgo biloba,
nicotine, some NSAIDs
• TTR may be decreased by insulin and
inflammation
Watanabe et al, 2001, Li et al, 2000
Alzheimer’s disease
and diet
• Lipids (saturated fat and PUFAs)
• Fish
• Homocysteine/methionine &
vitamins (folic acid, B12, B6)
(Kalmijn, et al 1997, 2000; Morris et al,
2003; Clarke et al, 1999; Friedland, 2003)
Homocysteine and TTR
• TTR may bind to homocysteine
(homocysteinylation, disulfide bonds to
cysteine), possibly interfering with
TTR’s ability to bind ABeta
Lim et al, 2003
Aging is inevitable?
• NO!
• It is an opportunity
Statins and AD
• Statins may lower AD risk
(Jick et al, 2001, Wolozin et al, 2001)
• Statins are anti-inflamatory as well as HMGCo A reductase inhibitors
(Hernadez-Presa et al, 2002)
• Plasma lipid levels may influence balance of
a,b,g secretases
(Beyreuther et al, 2001)
Factors influencing Abeta
clearance from brain to blood
Enhance ?
•
•
•
•
•
•
Anti-Ab Ab’s
TTR
Apo E e2-3
Apo J
Gelsolin
GM1
(Goldgaber et al, 1995;
Matsuoka et al, 2003)
Diminish ?
Apo E e4
High fat diet
High plasma lipid
levels
Insulin
Apo e4 has less affinity for
Abeta (Pillot et al, 1999)
Insulin decreases Abeta
elimination (Shiiki et al,
2004)
The major lipid binding domain of apo E is also the
C-terminal domain that binds ABeta (aa 244-271)
(Pillot et al, 1999, Huang et al, 2004)
Peripheral sink hypothesis
Peripheral anti-Ab antibody
alters CNS and plasma Ab
clearance and decreases
brain Ab burden in a mouse
model of Alzheimer’s disease
R.B. DeMattos, K.R. Bales, D.
J.Cummins, J-C. Dodart, S.M.
Paul, D.M. Holtzman
PNAS 98:8850, 2001
Alzheimer physiology –
choose your poison!
1. APP expression
2. APP cleavage
3. ABeta aggregation and toxicity
4. ABeta clearance from brain to blood
5. ABeta clearance from blood
Alzheimer physiology –
choose your poison!
1. APP expression
2. APP cleavage
3. ABeta aggregation and toxicity
4. ABeta clearance from brain to blood
5. ABeta clearance from blood