molecular mechanism for alzheimer’s disease : searching for the possible therapeutic targets...
TRANSCRIPT
![Page 1: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/1.jpg)
Molecular mechanism for Alzheimer’s disease: searching for the possible therapeutic targets
Sungkwon Chung Dept. of PhysiologySungkyunkwan Univ. School of Medicine
![Page 2: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/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: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/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 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.”
![Page 4: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/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: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/5.jpg)
Amyloid plaques and Neurofibrillary tangles
![Page 6: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/6.jpg)
Amyloid cascade hypothesis
![Page 7: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/7.jpg)
Amyloid Precursor Protein (APP) and its metabolites Citron, Nature Rev. Neurosci., 2004
APP → AβNotch1 → NICDp75NTR → p75-ICD
![Page 8: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/8.jpg)
![Page 9: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/9.jpg)
Roberson & Nucke, Science, 2006
![Page 10: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/10.jpg)
Q1:
Even though potent inhibitors for γ-secretase had been developed, it could not be used for the patients. Why?
![Page 11: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/11.jpg)
I. Functional role of presenilinin Ca2+ regulation
![Page 12: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/12.jpg)
The core of the -secretase complex
![Page 13: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/13.jpg)
Yoo et al., 2000
Presenilin as negative regulatorof capacitative Ca2+ entry (CCE)
![Page 14: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/14.jpg)
Effect of a CCE inhibitor, SKF, on A42 generation
![Page 15: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/15.jpg)
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.
![Page 16: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/16.jpg)
II. Finding molecular identity of CCE
![Page 17: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/17.jpg)
Down-regulation of IMIC in FAD PS mutants
A 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 (
pA
/pF
)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
of
IM
AX
MIC
![Page 18: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/18.jpg)
Recovery of IMIC from PS mutant cells by PIP2
![Page 19: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/19.jpg)
PP
P
PI(4,5)P2 PI(4)PPI(3,4,5)P3
PP P
IP3 + DAG PI(4,5)P2
PLC
![Page 20: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/20.jpg)
Down-regulation of PIP2 in PS mutant cells
![Page 21: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/21.jpg)
Correlation of the level of PIP2 and Aβ42 generation
![Page 22: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/22.jpg)
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.
![Page 23: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/23.jpg)
![Page 24: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/24.jpg)
III. Ginsenoside: Modulator for -secretase via PIP2
![Page 25: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/25.jpg)
Structure & function of gisenosides
![Page 26: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/26.jpg)
A42-lowering effect of Rg3
![Page 27: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/27.jpg)
A42-lowering effect of ginsenosides
![Page 28: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/28.jpg)
A42-lowering effect of Rg3, Rk1
![Page 29: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/29.jpg)
A42-lowering effect of Rg3 is specific for APP
![Page 30: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/30.jpg)
Increase of PI(4)P by Rg3
![Page 31: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/31.jpg)
Increase of PI(4)P by Rg3 via activation of PI4KII
![Page 32: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/32.jpg)
PI4KII decreases production of A42
![Page 33: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/33.jpg)
A42-lowering effect of Rg3 in vivo
![Page 34: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/34.jpg)
← PI4KII↑← Rg3
![Page 35: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/35.jpg)
IV. Activator for -secretase?
42, sAPP ELISA assay
![Page 36: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/36.jpg)
0
20
40
60
80
100
120
5g/ml25g/ml
concentration
A4
2 (%
of
con
tro
l)
CTL 100g/ml
MeOH extract (CN1-M)
BuOH (B)EtOAc (E)Hexane (H)Dichloromethane (M)
0
20
40
60
80
100
120
A4
2 (%
of
con
tro
l)
CTL B E H M
0
20
40
60
80
100
120
A4
2 (%
of
con
tro
l)
CTL E1 E2 E3 E4
HPCL Fractions (E1, E2, E3, E4)
0
20
40
60
80
100
120
A4
2 (%
of
con
tro
l)
CTL 1 2 3 4 5 6
E1 HPCL Fractions (1,2,3,4,5,6)
![Page 37: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/37.jpg)
0
20
40
60
80
100
50M10M 25M
concentration
A4
0 (%
of
con
tro
l)
CTL 5M0
20
40
60
80
100
50M10M 25M
concentration
A4
2 (%
of
con
tro
l)
CTL 5M
Dose dependent effect of E1-4-4 on A42 and A40 secretion
0
20
40
60
80
100
50M25M10M
concentration
sAP
P
(% o
f co
ntr
ol)
CTL 5M
![Page 38: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/38.jpg)
CN1-M-E1-4-4 increases sAPP, and decreases sAPP
![Page 39: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/39.jpg)
-secretase or-secretase
monoclonalantibody
Cell-free
![Page 40: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/40.jpg)
CN1-M-E1-4-4 may directly activates -secretase
![Page 41: Molecular mechanism for Alzheimer’s disease : searching for the possible therapeutic targets Sungkwon Chung Dept. of Physiology Sungkyunkwan Univ. School](https://reader030.vdocument.in/reader030/viewer/2022032805/56649ee45503460f94bf2878/html5/thumbnails/41.jpg)
Q2:
Amyloidogenic Aβ42 is produced by the activity of γ-secretase. However, activators for -secretase is considered as good therapeutic drug. Why?