molecular mechanism for alzheimer’s disease : searching for the possible therapeutic targets
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Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets. Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School of Medicine. Facts on Alzheimer’s disease (AD) It attacks and slowly steals the minds of its victims. - PowerPoint PPT PresentationTRANSCRIPT
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Molecular mechanism for Alzheimer’s disease: searching for the possible therapeutic targets
Sungkwon Chung Dept. of PhysiologySungkyunkwan Univ. School of Medicine
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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.
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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 Alzheimer’s is $174,000. Medicare costs for beneficiaries with Alzheimer’s are over $100 billion.
Alzheimer's disease 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.”
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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)
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Amyloid plaques and Neurofibrillary tangles
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Amyloid cascade hypothesis
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Amyloid Precursor Protein (APP) and its metabolites Citron, Nature Rev. Neurosci., 2004
APP → AβNotch1 → NICDp75NTR → p75-ICD
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Roberson & Nucke, Science, 2006
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Q1:
Even though potent inhibitors for γ-secretase had been developed, it could not be used for the patients. Why?
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I. Functional role of presenilinin Ca2+ regulation
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The core of the -secretase complex
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Yoo et al., 2000
Presenilin as negative regulatorof capacitative Ca2+ entry (CCE)
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Effect of a CCE inhibitor, SKF, on A42 generation
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Presenilin as part of -secretase
Presenilin as negative regulator of CCE
Leissring et al., J.C.B., 2000
Yoo et al., Neuron, 2000
CCE pathway may serve as a putative therapeutic target for Alzheimer’s disease.
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II. Finding molecular identity of CCE
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Down-regulation of IMIC in FAD PS mutantsA B
C D
0 150 300 450-120
-90
-60
-30
0
wt PS M146L L286V ∆E9
I MIC
(pA
/pF)
Time (s)
-40
-60
-80
-100
-120
*
∆E9
*
L286Vwt PS
I MIC (p
A/p
F)I C
RA
C(p
A/p
F)
0
-1
-2
-3
-4
∆E9wt PS L286V
0 150 300 450
-0.9
-0.6
-0.3
0.0
wt PS M146L L286V ∆E9
Time (s)
I /I
o
f IM
AX
MIC
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Recovery of IMIC from PS mutant cells by PIP2
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PP
P
PI(4,5)P2 PI(4)PPI(3,4,5)P3
PP P
IP3 + DAG PI(4,5)P2PLC
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Down-regulation of PIP2 in PS mutant cells
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Correlation of the level of PIP2 and Aβ42 generation
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TRPM7-like MIC currents underlie the mechanism for PS-mediated modulation of Ca2+ influx.
The down-regulation of PIP2 levels and the generation of Aβ42 were correlated.
Up-regulation of PIP2 levels will be a possible therapeutic target Alzheimer’s disease.
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III. Ginsenoside: Modulator for -secretase via PIP2
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Structure & function of gisenosides
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A42-lowering effect of Rg3
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A42-lowering effect of ginsenosides
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A42-lowering effect of Rg3, Rk1
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A42-lowering effect of Rg3 is specific for APP
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Increase of PI(4)P by Rg3
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Increase of PI(4)P by Rg3 via activation of PI4KII
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PI4KII decreases production of A42
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A42-lowering effect of Rg3 in vivo
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← PI4KII↑← Rg3
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IV. Activator for -secretase?
42, sAPP ELISA assay
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0
20
40
60
80
100
120
5g/ml25g/mlconcentration
A42
(% o
f con
trol)
CTL 100g/ml
MeOH extract (CN1-M)
BuOH (B)EtOAc (E)Hexane (H)Dichloromethane (M)
0
20
40
60
80
100
120
A42
(% o
f con
trol)
CTL B E H M
0
20
40
60
80
100
120
A42
(% o
f con
trol)
CTL E1 E2 E3 E4
HPCL Fractions (E1, E2, E3, E4)
0
20
40
60
80
100
120
A42
(% o
f con
trol)
CTL 1 2 3 4 5 6
E1 HPCL Fractions (1,2,3,4,5,6)
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0
20
40
60
80
100
50M10M 25M concentration
A40
(% o
f con
trol)
CTL 5M0
20
40
60
80
100
50M10M 25M concentration
A42
(% o
f con
trol)
CTL 5M
Dose dependent effect of E1-4-4 on A42 and A40 secretion
0
20
40
60
80
100
50M25M10M
concentration
sAPP
(%
of c
ontro
l)
CTL 5M
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CN1-M-E1-4-4 increases sAPP, and decreases sAPP
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-secretase or-secretase
monoclonalantibody
Cell-free
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CN1-M-E1-4-4 may directly activates -secretase
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Q2:
Amyloidogenic Aβ42 is produced by the activity of γ-secretase. However, activators for -secretase is considered as good therapeutic drug. Why?