nature may have the answers for alzheimer’s disease
DESCRIPTION
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 lossconfusion - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/1.jpg)
Nature may have the answers forAlzheimer’s disease
Sungkwon ChungDept. of PhysiologySungkyunkwan University School of Medicine
![Page 2: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/2.jpg)
Facts on Alzheimer’s disease (AD)
It attacks and slowly steals the minds of its victims. Symptoms of the disease include:
memory loss confusionimpaired judgment personality changesdisorientation 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.
![Page 3: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/3.jpg)
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 AgingAlzheimer'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.”
![Page 4: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/4.jpg)
Alzheimer’s disease
sporadic (late on-set): > 95% of patients - Epidemiological Factors
HypercholesterolaemiaHypertensionHyperrhomocysteinaemiaDiabete mellitusMetabolic syndromeSmokingSystemic inflammationIncreased 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)
![Page 5: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/5.jpg)
Amyloid plaques and Neurofibrillary tangles
![Page 6: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/6.jpg)
Selkoe, 2004
![Page 7: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/7.jpg)
Drug Approved for
Cholinesterase inhibitorsDonepezil Mild to moderate ADGalantamine Mild to moderate ADRivastigmine Mild to moderate ADTacrine Mild to moderate AD
NMDA receptor antagonistMemantine Moderate to severe AD
Food and Drug Administration approved treatments for AD
![Page 8: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/8.jpg)
A produced from Amyloid Precursor Protein (APP)
Presenilin (PS)
AICD
Notch1 → NICDp75NTR → p75-ICD
![Page 9: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/9.jpg)
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 A42
dependent
![Page 10: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/10.jpg)
Presenilin mutations linked to Familial Alzheimer's Disease cause an imbalance in PI(4,5)P2 metabolism (Landman et al., 2006)
PI4K
![Page 11: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/11.jpg)
Down-regulation of ITRPM7 in FAD PS mutants
A B
C
0 150 300 450-120
-90
-60
-30
0
wt PS M146L L286V ∆E9
I TR
PM
7 (
pA
/pF
)
Time (s)
-40
-60
-80
-100
-120
*
∆E9
*
L286Vwt PS
0 150 300 450
-0.9
-0.6
-0.3
0.0
wt PS M146L L286V ∆E9
Time (s)
C D
I TR
PM
7 (
pA
/pF
)
I TR
PM
7 (
pA
/pF
)
I TR
PM
7 (
pA
/pF
)
Whole-cellpatch clamp
![Page 12: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/12.jpg)
Down-regulation of PI(4,5)P2 in PS1, PS2 mutant cells
![Page 13: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/13.jpg)
Correlation of PI(4,5)P2 level and Aβ42 generation
PS1 WT PS1 E9
A4
2 (%
of E
9 co
ntr
ol) 100
80
60
40
20
00 5 10 20
PIP2 (M)15
E
C D
Landman et al., 2006
![Page 14: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/14.jpg)
Down-regulation of TRPM7 channel expressionincreases A42 production
C) D)
![Page 15: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/15.jpg)
FAD Mutant Presenilins
Increases in A42Altered PIP2 Metabolism
-independent dependent
TRPM7 channel / Ca2+ Defects
?
Correlation of PIP2 levels and Aβ42 generation Up-regulation of PIP2 levels will be a possible therapeutic
target for AD.
![Page 16: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/16.jpg)
I. Ginsenoside: increasing PIP2
Panax ginseng
![Page 17: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/17.jpg)
A42-lowering effect of Rg3
![Page 18: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/18.jpg)
Increase of PI(4)P and PI(4,5)P2 by Rg3
PI(4)P PI(4,5)P2
PI(4,5)P2
PI(4,5)P2
![Page 19: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/19.jpg)
Increase of PI(4)P by Rg3 via activation of PI4KII
![Page 20: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/20.jpg)
PI4KII decreases A42 production
![Page 21: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/21.jpg)
A42-lowering effect of Rg3 in vivo
![Page 22: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/22.jpg)
0
20
40
60
80
100
120
(g/ml)
S62
A4
2 (%
of
con
tro
l)
1051Cont
II. S62: increasing -cleavage
![Page 23: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/23.jpg)
sAPP
Cont C1 C2
C3 C4 C5
0.25 M
C1, C2 increase sAPP production
![Page 24: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/24.jpg)
0
20
40
60
80
100
C1 (g/ml)
5.00.50.10.050.010.0050
A4
2 (%
of
con
tro
l)
0
20
40
60
80
100
C1 (g/ml)
5.00.50.10.050.010.0050A4
0 (%
of
con
tro
l)
C1 decreases A42, A40 production
![Page 25: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/25.jpg)
0
20
40
60
80
100
C2 (g/ml)
5.00.50.10
A4
2 (%
of
con
tro
l)
0
20
40
60
80
100
C2 (g/ml)
5.00.50.10A4
0 (%
of
con
tro
l)
C2 decreases A42, A40 production with less potency
![Page 26: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/26.jpg)
sAPP
Cont
sAPP
Cont 0.5 0.05
C1 (g/ml)
5 0.5
C2 (g/ml)
Dose-dependent effect of C1, and C2 on the productionof sAPP (-secretase product)
![Page 27: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/27.jpg)
0
20
40
60
80
100
120
C1 (M)
510.50.10.050.01Cont
sAP
P-
sw (
% o
f co
ntr
ol)
0
200
400
600
800
1000
C1 (M)
510.50.10.050.01sA
PP
(% o
f co
ntr
ol)
Cont
C1 decreases -secretase product (sAPP), while increases secretase product (sAPP)
![Page 28: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/28.jpg)
Q2: Why an activator for -secretase is considered as good therapeutic drug?
![Page 29: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/29.jpg)
III. E3: decreasing APP level
![Page 30: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/30.jpg)
CTL
E144
0.1 0.5 1 5 0.25 0.25 μM
E2 E3
maAPP
β-tubulin
imAPP
0
20
40
60
80
100
E144 (M)510.50.1Cont
A4
2 (%
of
con
tro
l)
0
20
40
60
80
100
E144 (M)510.50.1Cont
A4
0 (%
of
con
tro
l)
E144, E3 decrease both mature, and immature forms of APP
![Page 31: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/31.jpg)
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.
![Page 32: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/32.jpg)
TransgenicTransgenic
Tg + Low Dose CJTg + Low Dose CJ Tg + High Dose Tg + High Dose CJCJ
BackgroundBackground
Recording: Acquisition Day 6Recording: Acquisition Day 6
![Page 33: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/33.jpg)
![Page 34: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/34.jpg)
BackgrounBackgroundd
TransgenicTransgenic
Low DoseLow Dose
High High DoseDose
Probe Phase (without Platform) :Probe Phase (without Platform) : Last day, Single trial
![Page 35: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/35.jpg)
40X 100X
Background
Transgenic
Low Dose
High Dose
![Page 36: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/36.jpg)
0
20
40
60
80
100
120(Cerebellum)
CJ150CJ50Cont
A4
2 (%
of
con
tro
l)
0
20
40
60
80
100
120(Hippocampus)
CJ150CJ50Cont
A4
2 (%
of
con
tro
l)
Effects of CJ on A42 levels
0
20
40
60
80
100
120*
(Cerebral Cortex)
CJ150CJ50Cont
A4
2 (%
of
con
tro
l)
![Page 37: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/37.jpg)
Q3: Why decreasing APP is considered as good therapeutic target?
![Page 38: Nature may have the answers for Alzheimer’s disease](https://reader035.vdocuments.us/reader035/viewer/2022062322/568150d2550346895dbef46e/html5/thumbnails/38.jpg)
Dept. of PhysiologySamsung Biomedical Research InstituteSungkyunkwan Univ. School of Medicine Sungkwon Chung Yoon Sun Chun Sung Hee Yun Hyun Geun Oh
Dept. of PathologyColumbia Univ. College of Physicians & Surgeons Tae-Wan Kim Gilbert Di Paolo Min Suk Kang
KIST Gangneung Institute Hyun Ok Yang