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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
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 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.”
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
Amyloid cascade hypothesis
Amyloid Precursor Protein (APP) and its metabolites Citron, Nature Rev. Neurosci., 2004
APP → AβNotch1 → NICDp75NTR → p75-ICD
Roberson & Nucke, Science, 2006
Q1:
Even though potent inhibitors for γ-secretase had been developed, it could not be used for the patients. Why?
I. Functional role of presenilinin Ca2+ regulation
The core of the -secretase complex
Yoo et al., 2000
Presenilin as negative regulatorof capacitative Ca2+ entry (CCE)
Effect of a CCE inhibitor, SKF, on A42 generation
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.
II. Finding molecular identity of CCE
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
Recovery of IMIC from PS mutant cells by PIP2
PP
P
PI(4,5)P2 PI(4)PPI(3,4,5)P3
PP P
IP3 + DAG PI(4,5)P2
PLC
Down-regulation of PIP2 in PS mutant cells
Correlation of the level of PIP2 and Aβ42 generation
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.
III. Ginsenoside: Modulator for -secretase via PIP2
Structure & function of gisenosides
A42-lowering effect of Rg3
A42-lowering effect of ginsenosides
A42-lowering effect of Rg3, Rk1
A42-lowering effect of Rg3 is specific for APP
Increase of PI(4)P by Rg3
Increase of PI(4)P by Rg3 via activation of PI4KII
PI4KII decreases production of A42
A42-lowering effect of Rg3 in vivo
← PI4KII↑← Rg3
IV. Activator for -secretase?
42, sAPP ELISA assay
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)
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
CN1-M-E1-4-4 increases sAPP, and decreases sAPP
-secretase or-secretase
monoclonalantibody
Cell-free
CN1-M-E1-4-4 may directly activates -secretase
Q2:
Amyloidogenic Aβ42 is produced by the activity of γ-secretase. However, activators for -secretase is considered as good therapeutic drug. Why?
