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