Download Activator & Inhibitor of Capacitative Ca2+ Entry : A

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
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.
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.”
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)
Amyloid plaques and Neurofibrillary tangles
Selkoe, 2004
Food and Drug Administration approved treatments for AD
Drug
Approved for
Cholinesterase inhibitors
Donepezil
Galantamine
Rivastigmine
Tacrine
Mild
Mild
Mild
Mild
to
to
to
to
moderate
moderate
moderate
moderate
AD
AD
AD
AD
NMDA receptor antagonist
Memantine
Moderate to severe AD
Ab produced from Amyloid Precursor Protein (APP)
AICD
Presenilin (PS)
Notch1 → NICD
p75NTR → p75-ICD
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?
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
-120
-100
ITRPM7 (pA/pF)
ITRPM7 (pA/pF)
0
-30
-60
wt PS
M146L
L286V
∆E9
-90
*
-80
*
-60
-40
-120
0
150
300
450
Time (s)
C
D
C
Whole-cell
patch clamp
ITRPM7 (pA/pF)
ITRPM7 (pA/pF)
0.0
-0.3
-0.6
wt PS
M146L
L286V
∆E9
-0.9
0
150
300
Time (s)
450
Down-regulation of PI(4,5)P2 in PS1, PS2 mutant cells
Correlation of PI(4,5)P2 level and Aβ42 generation
C
D
Ab42 (% of E9 control)
E
100
PS1 WT
PS1 E9
80
60
40
20
0
0
5
10
PIP2 (mM)
Landman et al., 2006
15
20
Down-regulation of TRPM7 channel expression
increases Ab42 production
C)
D)
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.
I. Ginsenoside: increasing PIP2
Panax ginseng
Ab42-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 Ab42 production
Ab42-lowering effect of Rg3 in vivo
II. S62: increasing -cleavage
Ab42 (% of control)
120
100
80
60
40
20
0
Cont
1
5
S62
10
(mg/ml)
C1, C2 increase sAPP production
Cont
C1
C2
C3
C4
C5
sAPP
0.25 mM
C1 decreases Ab42, Ab40 production
100
Ab40 (% of control)
Ab42 (% of control)
100
80
60
40
20
0
0
0.005
0.01
0.05
0.1
C1 (mg/ml)
0.5
5.0
80
60
40
20
0
0
0.005
0.01
0.05
0.1
C1 (mg/ml)
0.5
5.0
C2 decreases Ab42, Ab40 production with less potency
100
Ab40 (% of control)
Ab42 (% of control)
100
80
60
40
20
0
0
0.1
0.5
C2 (mg/ml)
5.0
80
60
40
20
0
0
0.1
0.5
C2 (mg/ml)
5.0
Dose-dependent effect of C1, and C2 on the production
of sAPP (-secretase product)
C1 (mg/ml)
Cont
0.5
0.05
sAPP
C2 (mg/ml)
Cont
sAPP
5
0.5
C1 decreases b-secretase product (sAPPb),
while increases -secretase product (sAPP)
1000
100
sAPP (% of control)
sAPPb-sw (% of control)
120
80
60
40
600
400
200
20
0
800
Cont
0
0.01
0.05
0.1
0.5
C1 (mM)
1
5
Cont
0.01
0.05
0.1
0.5
C1 (mM)
1
5
Q2: Why an activator for -secretase is considered as
good therapeutic drug?
III. E3: decreasing APP level
E144, E3 decrease both mature, and immature forms of APP
100
Ab40 (% of control)
Ab42 (% of control)
100
80
60
40
20
0
Cont
0.1
0.5
80
60
40
20
0
5
1
Cont
E2
E144
maAPP
imAPP
β-tubulin
0.1
0.5
E144 (mM)
E144 (mM)
CTL
0.1
0.5
1
5
0.25
E3
0.25 μM
1
5
Morris Water maze test : APPsw/PSEN1dE9, Male
-
Acquisition Phase (with Platform) : 4~6 days, 3 trials/day.
Probe Phase (without Platform) : Last day, Single trial.
Recording: Acquisition Day 6
Background
Transgenic
Tg + Low Dose CJ
Tg + High Dose CJ
Probe Phase (without Platform) : Last day, Single trial
Background
Transgenic
Low Dose
High
Dose
40X
Background
Transgenic
Low Dose
High Dose
100X
Effects of CJ on Ab42 levels
*
Ab42 (% of control)
120
(Cerebral Cortex)
100
80
60
40
20
0
Cont
CJ50
CJ150
120
120
100
80
60
40
20
0
(Cerebellum)
Ab42 (% of control)
Ab42 (% of control)
(Hippocampus)
Cont
CJ50
CJ150
100
80
60
40
20
0
Cont
CJ50
CJ150
Q3: Why decreasing APP is considered as good
therapeutic target?
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