Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Artificial gene synthesis wikipedia , lookup
Designer baby wikipedia , lookup
Gene expression profiling wikipedia , lookup
Gene expression programming wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Epigenetics of diabetes Type 2 wikipedia , lookup
Genome (book) wikipedia , lookup
Public health genomics wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
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