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Nature may have the answers for Alzheimer’s disease

Nature may have the answers for Alzheimer’s disease. Sungkwon Chung Dept. of Physiology Sungkyunkwan University School of Medicine. Facts on Alzheimer’s disease (AD) It attacks and slowly steals the minds of its victims. Symptoms of the disease include: memory loss confusion

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Nature may have the answers for Alzheimer’s disease

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  1. Nature may have the answers for Alzheimer’s disease Sungkwon Chung Dept. of Physiology Sungkyunkwan University School of Medicine

  2. Facts on Alzheimer’s disease (AD) • It attacks and slowly steals the minds of its victims. • Symptoms of the disease include: memory loss confusion impaired judgment personality changes disorientation loss of language skills. • Always fatal, Alzheimer's disease is the most common form of irreversible dementia. • 65-74 years : 10%, 75-84: 20%, 85 and older: 50% It is estimated that by 2020, 30 million people will be affected by this devastating disorder worldwide and by 2050, the number could increase to 45 million.

  3. Facts on Alzheimer’s disease (AD) • The average cost for nursing home care is $42,000 per year, and the average lifetime cost of care for an individual with AD is $174,000. Medicare costs for beneficiaries with AD are over$100 billion. • AD is a progressive, irreversible brain disorder with no known cause or cure. National Institute on Aging Alzheimer's Disease, Causes and Risk Factors “Scientists do not yet fully understand what causes Alzheimer's disease. There probably is not one single cause, • but several factors that affect each person differently.”

  4. Alzheimer’s disease  sporadic (late on-set): > 95% of patients - Epidemiological Factors Hypercholesterolaemia Hypertension Hyperrhomocysteinaemia Diabete mellitus Metabolic syndrome Smoking Systemic inflammation Increased fat intake and obesity  genetic (early on-set): < 5% of patients (FAD) - ApoE ε4 polymorphism - mutations in APP - mutations in presenilin 1, 2 (PS1, PS2)

  5. Amyloid plaques and Neurofibrillary tangles

  6. Selkoe, 2004

  7. Food and Drug Administration approved treatments for AD Drug Approved for Cholinesterase inhibitors Donepezil Mild to moderate AD Galantamine Mild to moderate AD Rivastigmine Mild to moderate AD Tacrine Mild to moderate AD NMDA receptor antagonist Memantine Moderate to severe AD

  8. Ab produced from Amyloid Precursor Protein (APP) AICD Presenilin (PS) Notch1 →NICD p75NTR →p75-ICD

  9. FAD Mutant Presenilins g-dependent Increases in Ab42 Q1: Even though potent inhibitors for γ-secretase had been developed, it could not be used for the patients. Why?

  10. Presenilin mutations linked to Familial Alzheimer's Disease cause an imbalance in PI(4,5)P2 metabolism (Landman et al., 2006) PI4K

  11. 0 0.0 -30 -0.3 ITRPM7 (pA/pF) -60 -0.6 wt PS -90 M146L -0.9 L286V ∆E9 -120 0 150 300 450 0 150 300 450 Time (s) -120 -100 * -80 wt PS * M146L L286V -60 ∆E9 -40 Time (s) L286V wt PS ∆E9 Down-regulation of ITRPM7 in FAD PS mutants A B ITRPM7 (pA/pF) C D C ITRPM7 (pA/pF) ITRPM7 (pA/pF) Whole-cell patch clamp

  12. Down-regulation of PI(4,5)P2 in PS1, PS2 mutant cells

  13. Correlation of PI(4,5)P2 level and Aβ42 generation E 100 80 60 Ab42 (% of DE9 control) 40 D C 20 0 0 10 15 20 5 PIP2 (mM) Landman et al., 2006

  14. Down-regulation of TRPM7 channel expression increases Ab42 production C) D)

  15. FAD Mutant Presenilins g-independent g-dependent Altered PIP2 Metabolism Increases in Ab42 ? TRPM7 channel / Ca2+ Defects • Correlation of PIP2 levels and Aβ42 generation •  Up-regulation of PIP2 levels will be a possible therapeutic target for AD.

  16. I. Ginsenoside: increasing PIP2 Panax ginseng

  17. A42-lowering effect of Rg3

  18. Increase of PI(4)P and PI(4,5)P2 by Rg3 PI(4,5)P2 PI(4)P PI(4,5)P2 PI(4,5)P2

  19. Increase of PI(4)P by Rg3 via activation of PI4KII

  20. PI4KII decreases A42 production

  21. A42-lowering effect of Rg3 in vivo

  22. II. S62: increasing a-cleavage

  23. C1, C2 increase sAPPa production C1 Cont C2 C3 C4 C5 sAPPa 0.25 mM

  24. C1 decreases Ab42, Ab40 production

  25. C2 decreases Ab42, Ab40 production with less potency

  26. Dose-dependent effect of C1, and C2 on the production of sAPPa (a-secretase product) C1 (mg/ml) Cont 0.5 0.05 sAPPa C2 (mg/ml) Cont 5 0.5 sAPPa

  27. C1 decreases b-secretase product (sAPPb), while increases a-secretase product (sAPPa)

  28. Q2: Why an activator for a-secretase is considered as good therapeutic drug?

  29. III. E3: decreasing APP level

  30. E144, E3 decrease both mature, and immature forms of APP E3 E2 E144 0.25 μM CTL 0.1 0.5 1 5 0.25 maAPP imAPP β-tubulin

  31. Morris Water mazetest : APPsw/PSEN1dE9, Male • Acquisition Phase (with Platform) : 4~6 days, 3 trials/day. • Probe Phase (without Platform) : Last day, Single trial.

  32. Recording: Acquisition Day 6 Transgenic Background Tg + Low Dose CJ Tg + High Dose CJ

  33. Probe Phase (without Platform) : Last day, Single trial Background Transgenic Low Dose High Dose

  34. Effects of CJ on Ab42 levels

  35. Q3: Why decreasing APP is considered as good therapeutic target?

  36. Dept. of Physiology Samsung Biomedical Research Institute Sungkyunkwan Univ. School of Medicine Sungkwon Chung Yoon Sun Chun Sung Hee Yun Hyun Geun Oh KIST Gangneung Institute Hyun Ok Yang Dept. of Pathology Columbia Univ. College of Physicians & Surgeons Tae-Wan Kim Gilbert Di Paolo Min Suk Kang

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