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Aging and disease    2020, Vol. 11 Issue (4) : 801-819     DOI: 10.14336/AD.2019.0813
Orginal Article |
Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway
Zhao Xia, Li Shuai, Gaur Uma, Zheng Wenhua*
Center of Reproduction, Development & Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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The most common form of dementia is Alzheimer’s disease which is characterized by memory loss and cognitive disorders. The pathogenesis of Alzheimer’s disease is not known at present but toxicity of amyloid-beta is one of the central hypotheses. Amyloid-beta can stimulate the production of reactive oxygen species (ROS), cause oxidative stress, damage mitochondrial, cause inflammatory reactions and activate apoptosis related factors which lead to the neuronal death. In this study, we found that artemisinin, a first line antimalarial drug used in clinic for decades, improved the cognitive functions in Alzheimer’s disease animal model 3xTg mice. Further study showed that artemisinin reduced the deposition of amyloid-beta and tau protein, reduced the release of inflammation factors and apoptosis factors, and thereby reduced the neuronal cell death. Western blot assay showed that artemisinin stimulated the activation of ERK/CREB signaling pathway. Consistent with these results, artemisinin concentration-dependently promoted the survival of SH-SY5Y cell against toxicity of amyloid-beta protein 1-42 induced ROS accumulation, caspase activation and apoptosis. Artemisinin also stimulated the phosphorylation of ERK1/2 and CREB in SH-SY5Y cells in time and concentration-dependent manner. Inhibition of ERK/CREB pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells in vitro as well as in vivo animal model 3xTg mice via, at least in part, the activation of the ERK/CREB pathway. Our findings also strongly support the potential of artemisinin as a new multi-target drug that can be used for preventing and treating the Alzheimer’s disease.

Keywords Alzheimer's disease      Artemisinin      cognitive behavior      amyloid beta      3×Tg mice      SH-SY5Ycells     
Corresponding Authors: Zheng Wenhua   
About author:

These authors contributed equally to this work.

Just Accepted Date: 12 October 2019   Issue Date: 30 July 2020
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Zhao Xia
Li Shuai
Gaur Uma
Zheng Wenhua
Cite this article:   
Zhao Xia,Li Shuai,Gaur Uma, et al. Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway[J]. Aging and disease, 2020, 11(4): 801-819.
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AntibodyCat. NOSourceCompany
APP/β-Amyloid (NAB228)2450MouseCST
β-Amyloid (1-42 Specific) (D3E10)12843RabbitCST
Tau (Tau46)4019MouseCST
Phospho-Tau (Ser396)11102RabbitSAB
phospho- Tau (thr212)1343547RabbitCALHIOCHEM
Phospho- Erk1/2 (Thr202/Tyr204)9101SRabbitCST
ERK 1/2 Polyclonal40902RabbitSAB
Cytochrome c (136F3)4280RabbitCST
GFAP (GA5)3670MouseCST
Pro-IL-1β Polyclonal Antibody41059RabbitSAB
Phospho-CREB (Ser133) (87G3)9191RabbitCST
Phospho-c-Jun (Ser73)9164RabbitCST
Table 1  Antibody Information.
(Three-Letter Code)
H - Asp - Ala - Glu - Phe - Arg - His - Asp - Ser - Gly - Tyr - Glu - Val - His - His - Gln - Lys - Leu - Val - Phe - Phe - Ala - Glu - Asp - Val - Gly - Ser - Asn - Lys - Gly - Ala - Ile - Ile - Gly - Leu - Met - Val - Gly - Gly - Val - Val - Ile - Ala - OH
Table 2  Detail information of β-Amyloid (1-42).
Figure 1.  Artemisinin improved the cognitive deficit of aged 3xTg mice. (A) Average escape latencies curve (four trials per day in the five consecutive days). (B) Time needed to find the hidden platform (escape latency) during the training. (C) Representative path tracking in the probe tests without hidden platform in day 6. (D) The average crossing platform times of each group mice within 60s in day 6. (E) Time spent in the target quadrant where the platform had been located in day 6. * p<0.05 or **p<0.01 3xTg vs WT; #p <0.05 3xTg vs 3xTg+ART.
Figure 2.  Artemisinin reduced Aβ deposition in aged 3xTg mice. (A) Immunohistochemistry (20x) and Immunofluorescence (10x) of Aβ in cortex and hippocampus; (B) Congo red staining (labeled amyloidosis) in cortex and hippocampus(40x); (C) Expression of APP/Aβ1-42 and the short APP fragments Aβ1-42 were determined by Western blot. (D-E) Quantitation of Western blots. **p<0.01 3xTg vs WT; #p<0.05 or ##<p: 0.01. 3xTg vs 3xTg+ART.
Figure 3.  Artemisinin reduced Tau deposition in aged 3xTg mice. (A) Immunohistochemistry (Cortex 20x, hippo10x) of p-Tau in cortex and hippocampus. (B) Expression level of p-Tau was detected by Western blot. (C-D) Quantitation of Western blots in B. **p<0.01 3xTg vs WT; #p<0.05 or ##<p: 0.01. 3xTg vs 3xTg+ART.
Figure 4.  Artemisinin attenuated the activation of glial cells, caspase activation and the expression of inflammatory molecules IL-1β in the brain of aged 3xTg mice. (A) Immunofluorescence and Immunohistochemistry of GFAP (Astrocyte marker) and AIF1 (Iba1, microglia marker) (40x). (B) Western blot analysis of the effect of ART on IL-1β and caspase1. (C-D) Quantitation of cleaved caspase1 and IL-1β in B. **p<0.01 3xTg vs WT; #p<0.05 or ##<p: 0.01. 3xTg vs 3xTg+ART.
Figure 5.  Artemisinin attenuated the histopathological changes and decreased neuronal apoptosis in 3xTg mice by activation of ERK. (A) HE staining showed the histopathological changes of neurons in 3xTg mice (40x). The cells were vacuolated, and ART increased cell number and reduced cell vacuolation; (B) Neuronal cell function was then examined using Nissl staining and our result indicated that artemisinin significantly improved neuronal function of 3xTg mice (40x); (C) Apoptosis determined by TUNEL staining in cortex of wild type and 3xTg mice treated as indicated (40x) . (D) Statistical analysis results of Nissl staining. (E) Quantitation of the deoxynucleotidyl transferased UTP nick-end labeling (TUNEL) staining in C. (F) The expression of p-ERK1/2, p-CREB, Bax, Bcl-2, Cytochrome C, cleaved caspase 9 and cleaved caspase-3 (active form of caspase 3) and GAPDH were detected by Western blot. **p<0.01 3xTg vs WT; #p<0.05 or ##<p: 0.01. 3xTg vs 3xTg+ART.
Figure 6.  Artemisinin concentration- and time-dependently reversed the decrease in cell viability. (A) Chemical structure of ART. (B) The cytotoxicity of ART, cells were treated with ART (3.125-200μM) for 24h and cell viability was measured using the MTT assay. (C) The cytotoxicity of Aβ1-42. Cells were treated with Aβ1-42 (0.5-8μM) for 24h and cell viability was measured using the MTT assay. (D) The effect of ART on cell viability. Cells were incubated with ART at indicated concentrations with or without 4μM Aβ1-42 for another 24h and cell viability was measured using the MTT assay. *P<0.05 or **P<0.01, or ***P<0.001, CTL vs Aβ1-42; #P<0.05 or ##P<0.01 Aβ1-42 vs Aβ1-42+ART.
Figure 7.  Artemisinin restored the mitochondrial membrane potential, and decreased ROS accumulation and reduced apoptosis induced by Aβ1-42 in SH-SY5Y cells. (A) Cells were pretreated with 12.5μM ART for 120min and then induced with or without 4μM Aβ1-42 for a further 24h. The decline in the mitochondrial membrane potential was reflected by the shift of fluorescence from red to green indicated by JC-1. Intracellular ROS level was measured by the CellROXs Deep Red Reagent. Nuclear morphology measured by Hoechst staining (40x). (B-D) Statistical analysis results of JC-1, ROS and Hoechst staining in A. (E) Photographs of representative cultures measured by Flow cytometry. (F) Statistical analysis results of Flow cytometry in E. (G) Expression of Bax, Bcl-2, and GAPDH were detected with Western blotting. (H) Quantification of representative protein band from Western blotting in G. *P<0.05 or **P<0.01, or ***P<0.001, CTL vs Aβ1-42; #P<0.05 or ##P<0.01 or ###P<0.001 Aβ1-42 vs Aβ1-42+ART.
Figure 8.  Artemisinin increased phosphorylation of ERK and CREB (ser133) in SH-SY5Y cells. (A) The SH-SY5Y cells were treated with ART for 120 min at different concentrations (3.15, 6.25, 12.5, 25 and 50 μM) and the expression of P-ERK1/2, p-CREB, P-C-Jun, Bcl2, Bax and GAPDH were detected by Western blot. (B-E) Statistical analysis results of A. (F) The SH-SY5Y cells were treated with ART for different times (0, 30, 60, 90, 120 and 180 min) at 12.5 μM and the expression of P-ERK1/2, p-CREB, P-C-Jun, Bcl2, Bax and GAPDH were detected by Western blot. (G-J) Statistical analysis results of F. *P<0.05 or **P<0.01, or ***P<0.001.
Figure 9.  ERK/CREB pathway mediated the protective effects of artemisinin in SH-SY5Y cells. (A-B) Cells, pretreated with 25 μM PD98059 (ERK inhibitor) for 60 min, were incubated with 4 μM Aβ1-42 in the presence or absence of 12.5μM ART. Apoptosis was measured by Tunel staining (40x). (C) Cell viability was measured by MTT assay. (D-E) Apoptosis was measured by Flow cytometry. (F) P-ERK1/2, P-CREB, Bax, Bcl2, Cytochrome C, cleaved caspase9 and cleaved caspase3 were measured by Western blot. (G-L) Statistical analysis results of P-ERK1/2, P-CREB, Bax, Bcl2, Cytochrome C, cleaved caspase9, cleaved caspase3. *: Difference between the Aβ1-42 group and WT groups; #: Difference between the Aβ1-42 and other groups; &: Difference between the ART+Aβ1-42 and other groups; **P<0.01, ***P<0.001, ##P<0.01, ###P<0.001, &P<0.05, &&P<0.01.
Figure 10.  The possible mechanism of artemisinin mediated neuroprotection against Aβ1-42-induced injury in neuronal cells and in 3xTg mice. Artemisinin stimulated ERK1/2 phosphorylation in neuronal cells and the brain of 3xTg mice, which results in activation of CREB/Bcl-2 survival pathway and inhibit apoptosis pathway. This process may reduce oxidative stress, correction of mitochondrial dysfunction. In addition, artemisinin also reduced the inflammatory release and reduced the deposition of amyloid plaques and neurofibrillary tangles.
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