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Nature may have the answers forAlzheimer’s disease
Sungkwon ChungDept. of PhysiologySungkyunkwan 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 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.
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.”
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)
Amyloid plaques and Neurofibrillary tangles
Selkoe, 2004
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
A produced from Amyloid Precursor Protein (APP)
Presenilin (PS)
AICD
Notch1 → NICDp75NTR → p75-ICD
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
Presenilin mutations linked to Familial Alzheimer's Disease cause an imbalance in PI(4,5)P2 metabolism (Landman et al., 2006)
PI4K
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
Down-regulation of PI(4,5)P2 in PS1, PS2 mutant cells
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
Down-regulation of TRPM7 channel expressionincreases A42 production
C) D)
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.
I. Ginsenoside: increasing PIP2
Panax ginseng
A42-lowering effect of Rg3
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
Increase of PI(4)P by Rg3 via activation of PI4KII
PI4KII decreases A42 production
A42-lowering effect of Rg3 in vivo
0
20
40
60
80
100
120
(g/ml)
S62
A4
2 (%
of
con
tro
l)
1051Cont
II. S62: increasing -cleavage
sAPP
Cont C1 C2
C3 C4 C5
0.25 M
C1, C2 increase sAPP production
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
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
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)
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)
Q2: Why an activator for -secretase is considered as good therapeutic drug?
III. E3: decreasing APP level
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
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.
TransgenicTransgenic
Tg + Low Dose CJTg + Low Dose CJ Tg + High Dose Tg + High Dose CJCJ
BackgroundBackground
Recording: Acquisition Day 6Recording: Acquisition Day 6
BackgrounBackgroundd
TransgenicTransgenic
Low DoseLow Dose
High High DoseDose
Probe Phase (without Platform) :Probe Phase (without Platform) : Last day, Single trial
40X 100X
Background
Transgenic
Low Dose
High Dose
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)
Q3: Why decreasing APP is considered as good therapeutic target?
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
