The therapeutic effect and molecular mechanism of astragalosides against b -amyloid–induced neurotoxicity in primary cortical neurons
SPEAKER: LI-SHENG CHANG
DATE: 104.02.13
COMMENTATOR: KAO-CHANG LIN, CHING-PING CHANG

Alzheimer’s Disease (AD):
 Dementia is a brain disorder that seriously affects a person’s memory, thinking, and reasoning skills.
 About 5 percent of men and women ages 65 to 74 have
Alzheimer’s disease, and nearly half of those age 85 and older may have the disease.
Alzheimer’s & Dementia 2014; 10:e47-e92

衛生福利部 http://www.tada2002.org.tw/tada_know_02.html

hippocampus
Amyloid Plaques
Neurofibrillary Tangles
Adv Med Sci. 2014; 60(1):76-82.
Alzheimer’s association (http://www.alz.org)

Hypothesis of the development of Alzheimer's disease
Neurosci Biobehav Rev. 2015; 49C:71-81.

b
Nature Reviews Neuroscience 2008; 9, 532-544

Nature Reviews Neuroscience 2008; 9, 532-544

Reproducing plaques and neurofibrillary tangles in transgenic mice
Nature Reviews Neuroscience 2008; 9, 532-544

Behavioural tests used to assess memory functions in AD mouse models
Nature Reviews Neuroscience 2008; 9, 532-544

• 乙醯膽鹼抑制劑（Cholinesterase inhibitors):
目前改善阿茲海默氏症患者知能藥物的主流。目前有donepezil (愛憶欣)及
Exelon(憶思能)與Riminyl三種。
• 乙醯膽鹼的前身 (Acetylcholine precursors):
有幾個小規模的lecithin及choline的臨床試驗，顯示無效。
• 尼古丁接受體促效劑（Nicotinic cholinergic receptor agonists):
兩個臨床試驗，其中一個發現尼古丁對學習能力有幫助，但記憶則沒有改善。
• Muscarinic cholinergic agonists:
因為乙醯膽鹼的腸胃及暈厥的副作用，所以臨床試驗沒再繼續。

To investigate a possible therapeutic candidate of drug for the treatment of Alzheimer's disease

• 多年生草本，豆科植物莢膜黃耆或蒙古黃耆之乾燥根
• 產於中國華北、東北、內蒙古和西北，主產於山西、黑龍
江、遼寧、河北等省
• 有益氣固表、斂汗固脫、托瘡生肌、利水消腫之功效
• 用于治療氣虛乏力，中氣下陷，表虛自汗，血虛萎黃，內
熱消渴，慢性腎炎，蛋白尿，糖尿病等。炙黃耆益氣補中，
生用固表托瘡。

有效成分
• 以現代科學分析技術已知具有：
1.
多醣類（ astragalan ，黃耆多醣）
2.
三萜皂苷類（ astragalosides ，黃耆總皂苷）
3.
黃酮類、胺基酸、酚酸、蔗糖、微量元素等成分
J. Agric. Food Chem., 50:4861-4866, 2002.

Pharmacological activities of Astragalus
• Astragaloside IV can protect the myocardial cells of rats from damage caused by lack of oxygen, and increase the content and activity of superoxide dismutase
(SOD) in the cytoplasm.
Clin Exp Pharmacol Physiol 2009;36(4):351-357.
• Astragaloside IV can improve fructopyranose-induced metabolic syndrome in rats by increasing levels of nitric metabolite and cyclic guanosine monophosphate, which manifested as reduction in blood pressure and improvement in insulin resistance.
Molecules 2011;16(5):3896-3907
• Astragaloside IV acted on HepG2 cells transfected with hepatitis-B virus, and secretion of hepatitis-B surface antigen, hepatitis-Be antigen as well as serum
HBV DNA levels were reduced.
Biol PharmBull 2009;32(1):132-135

Astragaloside IV Alleviates Early Brain Injury Following
Experimental Subarachnoid Hemorrhage in Rats subarachnoid hemorrhage (SAH) grade 1, no subarachnoid blood (scores=0); grade 2, minimal subarachnoid clots (scores=1); grade 3, moderate subarachnoid clots with recognizable arteries (scores=2) grade 4, blood clots covering all arteries
(scores=3).
Int J Med Sci. 2014; 11(10):1073-81.

Astragaloside in Alzheimer’s disease
SK-N-SH cells
PLoS One. 2014; 9(6):e98866.

Aim
To investigate the protective effects of astragalosides on A b
-induced primary cortical neuron death

Astragalosides reverse A b
-induced neuron cell death
120
100
80
60
40
20
0
#
# *
# *
# *
# *
Control 0 50 100 200 400 ug/ml AST
A b
25-35
# :P<0.05 VS.Control.
:P<0.05 VS.A
b
25-35
.

Cell morphology after AST treatment against on Ab-induced injury
Control A β 25-35 A β+50 ug/ml AST
A β+100 m g/ml AST A β+200 m g/ml AST A β+400 m g/ml AST
200x

Astragalosides reverse A b
-induced DNA fragmentation
100 bp marker
C 0 50 100
Aβ
25-35
200 400 ug/ml AST

Astragalosides reverses A b
-induced caspase 3 activation
Control
0 50
Aβ
25-35
100 200 400 ug/ml AST
Caspase-3
β-actin
1 25.6
6.6
3 1.6
2.4

(1)
Astragalosides exerts an inhibitory effect on A b
-
Induced apoptosis in primary cortical neuron

Astragalosides inhibits A b
-induced tau hyper-phosphorylation
C 0 50
Aβ
25-35
100 200 400 ug/ml AST p-Tau ( S199/202 )
1 17.5
6.3
3.8
3.2
3.8
p-Tau ( T231 )
1 4.9
1.1
0.7
0.8
1.2
Total-Tau
Synaptophysin
1 0.2
0.7
0.6
0.8
0.9
β-actin

Astragalosides restores A b
-induced synapse loss
MAP2 Synaptophysin DAPI Meraged
Control
Aβ
Aβ+ 50 ug/ml
AST
Aβ+ 100 ug/ml
AST
Aβ+ 200 ug/ml
AST
Aβ+ 400 ug/ml
AST

(2)
AST inhibits A b
-induced tau hyperphosphorylation and maintains neuronal synapse

ERK
?
AST Activation
Inhibition
β-amyloid deposition
?
PI3K/Akt
Tau hyperphosphorylation
β -catenin
Mitochondrial dysfunction
Neurofibrillary tangles
Apoptosis