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 lossconfusion impaired judgment personality changes disorientationloss 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. DrugApproved for Cholinesterase inhibitors DonepezilMild to moderate AD GalantamineMild to moderate AD RivastigmineMild to moderate AD TacrineMild to moderate AD NMDA receptor antagonist MemantineModerate to severe AD Food and Drug Administration approved treatments for AD

8. A  produced from Amyloid Precursor Protein (APP) Presenilin (PS) AICD Notch1 → NICD p75 NTR → p75-ICD

9. Q1: Even though potent inhibitors for γ-secretase had been developed, it could not be used for the patients. Why? FAD Mutant Presenilins Increases in A  42  dependent

10. Presenilin mutations linked to Familial Alzheimer's Disease cause an imbalance in PI(4,5)P 2 metabolism (Landman et al., 2006) PI4K

11. Down-regulation of I TRPM7 in FAD PS mutants AB C 0150300450 -120 -90 -60 -30 0 wt PS M146L L286V ∆E9 I TRPM7 (pA/pF) Time (s) -40 -60 -80 -100 -120 * ∆E9 * L286V wt PS 0150300450 -0.9 -0.6 -0.3 0.0 wt PS M146L L286V ∆E9 Time (s) C D I TRPM7 (pA/pF) Whole-cell patch clamp

12. Down-regulation of PI(4,5)P 2 in PS1, PS2 mutant cells

13. Correlation of PI(4,5)P 2 level and Aβ42 generation A  42 (% of  E9 control) 100 80 60 40 20 0 0 5 1020 PIP 2 (  M) 15 E C D Landman et al., 2006

14. Down-regulation of TRPM7 channel expression increases A  42 production C) D)

15. FAD Mutant Presenilins Increases in A  42 Altered PIP2 Metabolism  -independent  dependent TRPM7 channel / Ca 2+ Defects ?  Correlation of PIP 2 levels and Aβ42 generation  Up-regulation of PIP 2 levels will be a possible therapeutic target for AD.

16. I. Ginsenoside: increasing PIP 2 Panax ginseng

17. A  42-lowering effect of Rg3

18. Increase of PI(4)P and PI(4,5)P 2 by Rg3 PI(4)P PI(4,5)P 2

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  -cleavage

23. sAPP  Cont C1 C2C3C4C5 0.25  M C1, C2 increase sAPP  production

24. C1 decreases A  42, A  40 production

25. C2 decreases A  42, A  40 production with less potency

26. sAPP  Cont sAPP  Cont0.50.05 C1 (  g/ml) 50.5 C2 (  g/ml) Dose-dependent effect of C1, and C2 on the production of sAPP  (  -secretase product)

27. C1 decreases  -secretase product (sAPP  ), while increases  secretase product (sAPP  )

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

29. III. E3: decreasing APP level

30. CTL E144 0.10.5150.25 0.25 μM E2 E3 maAPP β-tubulin imAPP E144, E3 decrease both mature, and immature forms of APP

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

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

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

35. 40X100X Background Transgenic Low Dose High Dose

36. Effects of CJ on A  42 levels

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

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