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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 75  |  Page : 552-557  

Tanshinone IIA alleviates amyloid β-Induced neurotoxicity of SH-SY5Y cells through GSK-3β pathway


Department of Pharmacology, Anhui Xinhua University, Hefei, Anhui Province, China

Date of Submission12-Jun-2020
Date of Decision06-Jul-2020
Date of Acceptance09-Mar-2021
Date of Web Publication11-Nov-2021

Correspondence Address:
Rongrong Huang
Department of Pharmacology, Anhui Xinhua University, No. 555 Wangjiang West Road, Hefei, Anhui Province 230088
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pm.pm_249_20

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   Abstract 


Background: The deposition of amyloid β (Aβ) proteins and hyperphosphorylation of tau proteins are the two notable features of Alzheimer's disease. During the past decades, novel drug candidates have been found from natural herbs and its derived compounds due to their broad spectra of therapeutic effects with low toxicity. Among the different compounds studied, tanshinone IIA, which is derived from Salvia miltiorrhiza, has been reported to attenuate Aβ-induced neurotoxicity. Materials and Methods: In this study, we studied the effects of tanshinone IIA on the neurotoxicity, proliferation, and apoptosis of Aβ25–35-induced SH-SY5Y cells. We applied various methods such as Western blot, fluorescence staining, and flow cytometry. We analyzed the tau phosphorylation and inflammatory response of SH-SY5Y cells, and we further discuss the relationship between phosphorylated tau and GSK-3β pathway. Results: Tanshinone IIA promoted proliferation and inhibited neurotoxicity of Aβ25–35-induced SH-SY5Y cells. In addition, it downregulated the level of phosphorylation of tau protein, leading to the inhibition of inflammatory response. The Y216 phosphorylation level of GSK-3β was downregulated by tanshinone IIA, whereas the S9 phosphorylation level was upregulated. Conclusion: The results of this study provide evidence that tanshinone IIA exerts its beneficial effects by attenuating the neurotoxicity induced by Aβ25–35 through the GSK-3β pathway.

Keywords: Alzheimer's disease, amyloid β peptide, GSK-3β pathway, SH-SY5Y cells, tanshinone IIA, tau phosphorylation


How to cite this article:
Huang R, Lu S. Tanshinone IIA alleviates amyloid β-Induced neurotoxicity of SH-SY5Y cells through GSK-3β pathway. Phcog Mag 2021;17:552-7

How to cite this URL:
Huang R, Lu S. Tanshinone IIA alleviates amyloid β-Induced neurotoxicity of SH-SY5Y cells through GSK-3β pathway. Phcog Mag [serial online] 2021 [cited 2021 Nov 28];17:552-7. Available from: http://www.phcog.com/text.asp?2021/17/75/552/330203



SUMMARY

  • Tanshinone IIA promoted proliferation and inhibited neurotoxicity of Aβ25–35-induced SH-SY5Y cells. In addition, it downregulated the level of phosphorylation of tau protein, leading to the inhibition of inflammatory response. The Y216 phosphorylation level of GSK-3β was downregulated by tanshinone IIA, whereas the S9 phosphorylation level was upregulated.




Abbreviations used: Aβ: The deposition of amyloid β; AD: Alzheimer's disease


   Introduction Top


Alzheimer's disease (AD), the most common type of senile dementia, has several pathological features, including neuronal degeneration, intracellular neurofibrillary tangles, and extracellular senile plaque deposition.[1] Although a large number of investigators have been searching for effective methods for the diagnosis and treatment of this disease, the pathogenesis of AD is still not clear. In the pathological process known so far, the dynamic balance between the production and clearance of amyloid β (Aβ) peptides is destabilized, resulting in the abnormal accumulation of Aβ peptides. The complex cascade of reactions triggers multiple processes, including plaque formation, tau protein hyperphosphorylation, glial cell proliferation, and inflammation, which results in nerve cell dysfunction.[2] Therefore, Aβ is a promising target in the treatment of AD, which has been widely investigated.[3],[4]

During the past few decades, great efforts have been made to develop drugs for the prevention and treatment of AD. So far, numerous drug candidates have been studied, such as natural compounds derived from herbs.[5],[6],[7] Among these, tanshinone IIA [Figure 1]a, a diterpenoid compound isolated from Salvia miltiorrhiza, is widely used in the treatment of cardiovascular diseases. This compound shows antiapoptosis, anti-inflammation, and antioxidant activity.[8],[9] Recently, several studies have revealed their positive effects of tanshinone IIA on diseases affecting the nervous system, demonstrating the therapeutic potential of tanshinone IIA in preventing and alleviating AD. For example, Qian et al.[10] demonstrated that tanshinone IIA protects neurons against Aβ-induced neuronal injury through the activation of the Bcl-xL pathway. Jiang et al.[11] found that tanshinone IIA decreases the release of nitric oxide, peroxynitrite, and anion, as well as the expression of inducible nitric oxide synthase, matrix metalloprotein type 2, and nuclear factor-kappa B in the AD rat model. In a recent study, Geng et al.[12] reported that tanshinone IIA reduced the level of Aβ-induced neurotoxicity due to its superior antioxidant properties.
Figure 1: Effects of tanshinone IIA on the proliferation of SH-SY5Y cells injured by Aβ25–35. (a) Chemical structure of tanshinone IIA. After treating with sodium 4-phenylbutyrate (5 mM) or tanshinone IIA (2.5 μM, 5 μM, and 10 μM), the proliferation of Aβ25–35-injured SH-SY5Y cells was measure by (b) CCK8 assay, (c) EdU staining, and (d) Western blot for cell proliferation factor (Ki-67 and PCNA). Statistical data are presented as mean ± standard deviation **P < 0.01, versus control group. #P < 0.05, ##P < 0.01, versus Aβ group. The experiments were independently repeated three times

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In this study, the neuroprotective effects of tanshinone IIA on Aβ-induced SH-SY5Y cells were investigated. The proliferation of Aβ-induced SH-SY5Y cells was found to be promoted by tanshinone IIA. In addition, the apoptosis of Aβ-induced SH-SY5Y cells was inhibited. Moreover, we demonstrated that tanshinone IIA downregulated the phosphorylation level of tau protein in these cells, leading to the inhibition of the inflammatory response. GSK-3β pathway, which could cause hyperphosphorylation tau, was further demonstrated to be regulated corresponding to the tanshinone IIA treatment. Our research may provide proof-of-principle evidence of the mechanism through which tanshinone IIA prevents Aβ-induced neurotoxicity of SH-SY5Y cells.


   Materials and Methods Top


Compounds

Tanshinone IIA (C19H18O3, FW: 294.34, purity >98%) was obtained from MedChemExpress (Shanghai, China). Aβ25–35 peptide (purity >95%) was purchased from GL Biochem Inc. (Shanghai, China). Sodium 4-phenylbutyrate (4-PBA) (C10H12O2, FW: 164.20, purity >98%) was obtained from Sigma-Aldrich (Shanghai, China).

Cell treatment

For the establishment of Aβ25–35-induced SH-SY5Y cell model, Aβ25–35 was diluted to 1 mM by distilled water for a stock solution and then cultured in a 37°C incubator for 3 days to aggregate oligomers before use The activated Aβ25–35 was diluted to 25 μM and stored at −20°C. Cells (1 × 105) were seeded in a 6-well plate (1 mL) and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS). When the confluency reached 70%, the medium was replaced with a serum-free culture medium and incubated for 24 h. Then, Aβ25–35 (25 μM) was added and incubated for another 24 h for use in subsequent experiments. To understand the role of tanshinone IIA, the experimental groups were set up, including a blank control group, the negative control group (phosphate-buffered saline [PBS]), tanshinone IIA (2.5, 5, and 10 μM) experimental group, and positive control group (4-PBA). The effects of 4-PBA were determined by treating the cells with 5 mM 4-PBA.

Cell viability analysis

Cells (5 × 103) were seeded in 96-well plate (100 μL) and cultured in RPMI 1640 medium supplemented with 10% FBS. When the confluency reached 70%, the medium was replaced with a medium containing different concentrations of tanshinone IIA. After 24 h of incubation, 20 μL CCK-8 solution (Beyotime Biotechnology, Nantong, China) was added to each well. After incubating for 1 h, the absorbance was detected at 450 nm by a microplate reader (Thermo Fisher, Massachusetts, USA).

Quantitative real-time polymerase chain reaction

SH-SY5Y cells (1 × 105) were seeded in a 6-well plate (1 mL) and treated according to the experimental group. When the confluency reached 90%, the RNA extraction was performed by TRIzol reagent as described previously.[13] The concentration of RNA was measured by spectrophotometer, and all samples were balanced by reverse transcription with a cDNA synthesis kit (Fermentas, St. Leon-Rot, Germany). After the implementation of a real-time reverse-transcription polymerase chain reaction, the cycle threshold (CT) value of the target gene expression was obtained and compared with the control group. GAPDH was used as the internal control gene. The relative quantitative analysis was conducted by 2–ΔΔCT method.

EdU staining

SH-SY5Y cells (1 × 105) were seeded in a 6-well plate (1 mL) and treated according to the experimental group. After treatment, the cells were fixed with 4% paraformaldehyde and permeated with 0.5% Triton X-100. After washing (thrice) with PBS containing 3% BSA, the EdU staining solution (US Everbright, Suzhou, China) was added and incubated at room temperature (RT) for 30 min. Subsequently, the nucleus was counterstained with DAPI, and the cells were observed with a fluorescence microscope (IX73, Olympus, Japan).

Cell apoptosis analysis

Cells (1 × 105) were seeded in a 6-well plate (1 mL) and cultured for 24 h. After the treatment of the cells as mentioned above, the cells were collected (×1000 rpm for 5 min) and washed with PBS. Then, the cells were resuspended with 5 μL Annexin V-fluorescein isothiocyanate (FITC) and 5 μL of propidium iodide (PI) and incubated at RT for 15 min. Flow cytometric analysis was conducted by a FACSCalibur flow cytometer (BD Bioscience, New Jersey, USA).

TUNEL analysis

Cells (1 × 105) were seeded in a 6-well plate (1 mL) and treated according to the experimental group. After treatment, the cells were fixed with 4% paraformaldehyde and permeated with 0.5% Triton. After washing (thrice) with PBS containing 3% BSA, cells were treated with TUNEL staining. The experiment was conducted according to the instructions of the TUNEL Assay Kit (Abcam, Shanghai, China). Finally, the nuclei were counterstained with DAPI, and the cells were observed with a fluorescence microscope (IX73, Olympus, Japan).

Enzyme-linked immunosorbent assay

The inflammatory factors in the supernatant of the cell culture medium were detected according to the instructions. All enzyme-linked immunosorbent assay (ELISA) kits were purchased from R&D Systems (Shanghai, China). Finally, the value of optical density for each well was measured by a microplate reader at 450 nm wavelength (Thermo Fisher, Massachusetts, USA).

Immunofluorescence analysis

The cells were inoculated into a Petri dish with pretreated glass slides. When the confluency reached 80%, the cells were fixed with 4% paraformaldehyde and permeated with 0.5% Triton. Subsequently, the cells were washed (thrice) with PBS and blocked with 3% (w/v) BSA at 4°C overnight. Then, the cell was incubated with primary antibodies against p-GSK-3β-Y216 (1:500 dilution) and p-GSK-3β-S9 (1:500 dilution) at 4°C overnight. All antibodies were purchased from Abcam (Shanghai, China). After incubating with FITC-conjugated secondary antibodies (1:200 dilution, Proteintech, Wuhan, China) at RT for 1 h, the slides were observed with a fluorescence microscope (IX73, Olympus, Japan).

Statistical analysis

Data were presented in the form of mean ± standard deviation. Statistical analysis was performed by GraphPad Prism 6 (GraphPad Software, Inc., San Diego, CA, USA), and differences between groups were analyzed by one-way analysis of variance and Dunnett's multiple comparison tests. A P < 0.05 was considered statistically significant.


   Results Top


Tanshinone IIA promotes the proliferation of amyloid β25–35-induced SH-SY5Y cells

In this study, we studied the effects of tanshinone IIA on the proliferation of SH-SY5Y cells. As revealed in [Figure 1]b, the viability of SH-SY5Y cells was significantly inhibited, indicating that the cell model was successfully established. These results also suggested that 4-PBA (an inhibitor of endoplasmic reticulum stress) significantly attenuated the Aβ25–35-induced neurotoxicity [P < 0.05, vs. Aβ group, [Figure 1]b. Of note, both 5 μM and 10 μM tanshinone IIA significantly attenuated the Aβ25–35-induced neurotoxicity [P < 0.05, vs. Aβ group, [Figure 1]b]. Moreover, EdU staining was also employed to analyze the proliferation of Aβ25–35-induced SH-SY5Y cells. The results suggested that tanshinone IIA significantly promoted the proliferation of Aβ-induced SH-SY5Y cells [Figure 1]c. Moreover, tanshinone IIA promoted the proliferation of SH-SY5Y cells. Next, we investigated the expression of the cell proliferation factor of Aβ25–35-induced SH-SY5Y cells. As demonstrated in [Figure 1]d, tanshinone IIA significantly increased the expression levels of Ki-67 and PCNA [Figure 1]d. In addition, tanshinone IIA exhibited comparable effects with 4-PBA on the proliferation of Aβ25–35-induced SH-SY5Y cells. Overall, our results show that tanshinone IIA promotes the proliferation of Aβ25–35-induced SH-SY5Y cells.

Tanshinone IIA rescued amyloid β25–35-induced apoptosis of SH-SY5Y cells

In this study, we studied the effects of tanshinone IIA on the apoptosis of SH-SY5Y cells using TUNEL analysis. According to our results, DNA fragments with 3'-OH cohesive terminus of SH-SY5Y cells were in increased quantities in response to Aβ treatment, which indicates that the apoptosis of Aβ25–35-induced SH-SY5Y cells was upregulated. In contrast, tanshinone IIA also decreased the DNA fragments in Aβ25–35-induced SH-SY5Y cells [Figure 2]a. In addition, the results of Annexin V/PI staining suggested that tanshinone IIA significantly decreased the level of apoptosis [P < 0.05, vs. Aβ group, [Figure 2]b. In this study, we analyzed the apoptotic pathway via Western blot analysis. According to the results of Western blot analysis, tanshinone IIA downregulated the expression of Bax and upregulated the expression of Bcl-2 proteins [P < 0.01, vs. Aβ group, [Figure 2]c]. Moreover, it exhibited comparable effects with 4-PBA on the apoptosis of Aβ25–35-induced SH-SY5Y cells. Overall, these data indicate that tanshinone IIA rescued apoptosis in Aβ25–35-induced SH-SY5Y cells.
Figure 2: Effects of tanshinone IIA on the apoptosis of SH-SY5Y cells injured by Aβ25–35. After treating with sodium 4-phenylbutyrate (5 mM) or indicated concentrations of tanshinone IIA, the apoptosis of Aβ25–35-injured SH-SY5Y cells was measure by (a) TUNEL assay, (b) flow cytometry with Annexin V/PI Staining and (c) Western Blot for apoptosis pathway, including Bax and Bcl-2. Statistical data are presented as mean ± standard deviation **P < 0.01, versus control group. #P < 0.05, ##P < 0.01, versus Aβ group. The experiments were independently repeated three times

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Tanshinone IIA inhibits tau phosphorylation and inflammatory response in amyloid β25–35-induced SH-SY5Y cells

Next, we analyzed the level of tau phosphorylation via Western blot analysis. According to our results, the phosphorylation of tau at Ser205, Ser396, and Ser413 was all significantly upregulated by Aβ25–35 peptides [P < 0.01, vs. control group, [Figure 3]a, and tanshinone IIA remarkably inhibited the phosphorylation of tau at these sites. These results show that tanshinone IIA downregulated the Aβ25–35-induced neuroinflammation in SH-SY5Y cells. Hence, the expression of inflammatory cytokines was further analyzed by ELISA and qPCR. As revealed in [Figure 3]b and [Figure 3]c, the protein and mRNA levels of inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, IL-1β, and IL-10) were upregulated by Aβ25–35 peptides (P < 0.01, vs. control group). Moreover, tanshinone IIA decreased the secretion of the aforementioned inflammatory cytokines from the Aβ25–35-induced SH-SY5Y cells [Figure 3]b. In addition, the mRNA level of inflammatory factors was also markedly downregulated by tanshinone IIA [P < 0.05, vs. Aβ group, [Figure 3]c]. Overall, tanshinone IIA exhibited comparable effects with 4-PBA on the tau phosphorylation and inflammation in the Aβ25–35-induced SH-SY5Y cells. These results indicated that tanshinone IIA inhibited the phosphorylation level of tau, leading to the downregulation of the Aβ-induced neuroinflammation.
Figure 3: Effects of tanshinone IIA on phosphorylation of tau protein and inflammatory factors expression of SH-SY5Y cells injured by Aβ25–35. After treating with sodium 4-phenylbutyrate (5 mM) or indicated concentrations of tanshinone IIA on Aβ25–35-injured SH-SY5Y cells, (a) protein levels of phosphorylated tau proteins (Ser205, Ser396, and Ser413), and total tau protein (Tau-5) were measured by Western blot, (b) expression of inflammatory factors (TNF-α, IL-6, IL-1β, and IL-10) was measured by ELISA, and (c) mRNA expression levels of inflammatory factors (TNF-α, IL-6, IL-1β, and IL-10) were measured by qPCR. Statistical data are presented as mean ± standard deviation **P < 0.01, versus control group. #P < 0.05, ##P < 0.01, versus Aβ group. The experiments were independently repeated three times

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Tanshinone IIA regulates GSK-3β pathway of amyloid β-induced SH-SY5Y cells

In this study, we investigated the activation of GSK-3β pathway, which could cause hyperphosphorylation of tau. First, the fluorescence intensity of p-GSK-3β-Y216 was increased after inducing the cells with Aβ25–35 peptides; however, the fluorescence intensity of p-GSK-3β-S9 was decreased [Figure 4]a. Furthermore, our results show that the expression of p-GSK-3β-Y216 was downregulated in Aβ25–35-induced SH-SY5Y cells by tanshinone IIA, whereas the intensity of p-GSK-3β-S9 was increased [Figure 4]a. Our findings show that tanshinone IIA might regulate the level of phosphorylation of GSK-3β. Therefore, we further analyzed the level of tau phosphorylation. According to our results, the Y216 phosphorylation level of GSK-3β was downregulated by tanshinone IIA, whereas the S9 phosphorylation level was dramatically upregulated [Figure 4]b. Of note, all these effects of tanshinone IIA were in a dose-dependent manner and were comparable with the positive drug 4-PBA. These results indicated that tanshinone IIA regulated the GSK-3β pathway of Aβ-induced SH-SY5Y cells, leading to a decrease in the phosphorylation level of tau.
Figure 4: Effects of tanshinone IIA on GSK-3β phosphorylation of SH-SY5Y cells injured by Aβ25–35. After treating with sodium 4-phenylbutyrate or indicated concentrations of tanshinone IIA on Aβ25–35-injured SH-SY5Y cells, (a) phosphorylation levels of GSK-3β protein were measured by immunofluorescence and (b) protein levels of phosphorylated GSK-3β proteins (Y216 and S9) and total GSK-3β proteins were measured by Western BLOT. Statistical data are presented as mean ± standard deviation n = 3, **P < 0.01, versus control group. #P < 0.05, ##P < 0.01, versus Aβ group. The experiments were independently repeated three times

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   Discussion Top


Neurodegenerative disease is one of the most severe challenges for human beings. To date, the pathogenesis of AD has not been fully understood. Of note, various natural compounds derived from herbs have been found to have excellent biological activity, which could be the potential candidates for the treatment of AD.[5],[6],[14] Among these natural compounds, tanshinone IIA is an interesting regulatory molecule for AD, which had been reported to attenuate Aβ-induced neurotoxicity.[12],[15]

Aβ-induced neurotoxicity is one of the most important pathological features of AD.[1] Alleviating its toxicity is an essential indicator for evaluating drug candidates of AD. In this study, we demonstrate that tanshinone IIA possessed an excellent pharmacological activity to prevent Aβ-induced neurotoxicity of SH-SY5Y cells. In general, this effect is usually generated by inhibiting the apoptotic pathway.[16] By analyzing the typical apoptotic characteristics and the critical factors involved in the apoptotic pathway, our results showed that tanshinone IIA indeed inhibited the Aβ-induced apoptosis of SH-SY5Y cells. These findings indicated that tanshinone IIA had the potential pharmacological activity to become a drug candidate for AD.

Tau protein is a phosphate-containing essential protein in maintaining the stability of microtubule and nerve cell function, which participates in the growth, development, and formation of axons.[17],[18] Studies have shown that the level of tau protein phosphorylation in the brain of patients may become an index for early diagnosis of AD.[19] The pathological mechanism of tau phosphorylation has a significant relationship between Aβ peptides. Our findings suggest that tanshinone IIA inhibited the Ser205, Ser396, and Ser413 phosphorylation of tau protein. However, neuroinflammation is another typical pathological feature in the occurrence and development of AD in addition to Aβ deposition and tau hyperphosphorylation.[20],[21] Here, we found that the protein and mRNA levels of an inflammatory factor, including TNF-α, IL-6, IL-1β, and IL-10, were downregulated by tanshinone IIA in Aβ-induced SH-SY5Y cells. These findings show that tanshinone IIA decreased the level of phosphorylation of tau, leading to the amelioration of inflammatory response in the Aβ-induced SH-SY5Y cells.

GSK-3β is a critical serine/threonine protein kinase, which plays a crucial role in neuronal development, neurophysiological function, and the pathogenesis of some nervous system diseases.[22] GSK-3β plays a critical role in the production of toxic Aβ protein, abnormal hyperphosphorylation of tau protein, dystrophic neuritis, and impaired neuronal function. Hence, it plays a vital role in pathological transformations. Sengupta et al.[23] found that GSK-3β participates in the phosphorylation of multiple sites of tau protein activation. Hoshi et al.[24] found that toxic Aβ rapidly increased the phosphorylation of GSK-3β, which contributed to the abnormal hyperphosphorylation of tau protein and neuronal death. In addition, Saeki et al.[25] suggested that hyperphosphorylated tau protein activates GSK-3β via oxidative stress, inflammatory response, and apoptosis. However, the roles of tanshinone IIA on the regulation of the GSK-3β pathway of SH-SY5Y cells are not clear. According to our results, the Y216 phosphorylation level of GSK-3β was decreased by tanshinone IIA, whereas the S9 phosphorylation level was increased. These results show that tanshinone IIA regulated the GSK-3β pathway of Aβ-induced SH-SY5Y cells and decreased the phosphorylation level of the tau protein.


   Conclusion Top


Our findings demonstrated that tanshinone IIA alleviated neurotoxicity and hyperphosphorylated tau in SH-SY5Y cells induced by Aβ25–35 through the GSK-3β pathway, which may provide a novel insight to illustrate the therapeutic mechanism of tanshinone IIA on the AD.

Financial support and sponsorship

This work was supported by the Natural Science Foundation of Anhui Province Education Department (NO. KJ2015A298) and the Quality Engineering Project of Anhui Province Education Department (NO. 2018 mooc438).

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol 2018;25:59-70.  Back to cited text no. 1
    
2.
Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathol 2018;136:663-89.  Back to cited text no. 2
    
3.
Gouras GK, Olsson TT, Hansson O. β-Amyloid peptides and amyloid plaques in Alzheimer's disease. Neurotherapeutics 2015;12:3-11.  Back to cited text no. 3
    
4.
Sengupta U, Nilson AN, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 2016;6:42-9.  Back to cited text no. 4
    
5.
Afzal M, Redha A, AlHasan R. Anthocyanins potentially contribute to defense against Alzheimer's disease. Molecules 2019;24:4255.  Back to cited text no. 5
    
6.
Olasehinde TA, Olaniran AO, Okoh AI. Macroalgae as a valuable source of naturally occurring bioactive compounds for the treatment of Alzheimer's disease. Mar Drugs 2019;17:609.  Back to cited text no. 6
    
7.
Deshpande P, Gogia N, Singh A. Exploring the efficacy of natural products in alleviating Alzheimer's disease. Neural Regen Res 2019;14:1321-9.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Li ZM, Xu SW, Liu PQ. Salvia miltiorrhiza Burge (Danshen): A golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin 2018;39:802-24.  Back to cited text no. 8
    
9.
Zhou L, Zuo Z, Chow MS. Danshen: An overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 2005;45:1345-59.  Back to cited text no. 9
    
10.
Qian YH, Xiao Q, Xu J. The protective effects of tanshinone IIA on β-amyloid protein (1-42)-induced cytotoxicity via activation of the Bcl-xL pathway in neuron. Brain Res Bull 2012;88:354-8.  Back to cited text no. 10
    
11.
Jiang P, Li C, Xiang Z, Jiao B. Tanshinone IIA reduces the risk of Alzheimer's disease by inhibiting iNOS, MMP-2 and NF-κBp65 transcription and translation in the temporal lobes of rat models of Alzheimer's disease. Mol Med Rep 2014;10:689-94.  Back to cited text no. 11
    
12.
Geng L, Liu W, Chen Y. Tanshinone IIA attenuates Aβ-induced neurotoxicity by down-regulating COX-2 expression and PGE2 synthesis via inactivation of NF-κB pathway in SH-SY5Y cells. J Biol Res (Thessalon) 2019;26:15.  Back to cited text no. 12
    
13.
Zhang N, Li WW, Lv CM, Gao YW, Liu XL, Zhao L. miR-16-5p and miR-19b-3p prevent amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells. Neuroreport 2020;31:205-12.  Back to cited text no. 13
    
14.
Shi LY, Zhang L, Li H, Liu TL, Lai JC, Wu ZB, et al. Protective effects of curcumin on acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. Pharmacol Rep 2018;70:1040-6.   Back to cited text no. 14
    
15.
Yang W, Zhang J, Shi L, Ji S, Yang X, Zhai W, et al. Protective effects of tanshinone IIA on SH-SY5Y cells against oAβ 1-42-induced apoptosis due to prevention of endoplasmic reticulum stress. Int J Biochem Cell Biol 2019;107:82-91.  Back to cited text no. 15
    
16.
Song J, Park KA, Lee WT, Lee JE. Apoptosis signal regulating kinase 1 (ASK1): Potential as a therapeutic target for Alzheimer's disease. Int J Mol Sci 2014;15:2119-29.  Back to cited text no. 16
    
17.
Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 1984;259:5301-5.  Back to cited text no. 17
    
18.
Strömberg K, Eketjäll S, Georgievska B, Tunblad K, Eliason K, Olsson F, et al. Combining an amyloid-beta (Aβ) cleaving enzyme inhibitor with a γ-secretase modulator results in an additive reduction of Aβ production. FEBS J 2015;282:65-73.  Back to cited text no. 18
    
19.
Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: The story so far. Nat Rev Neurol 2016;12:15-27.  Back to cited text no. 19
    
20.
Savarin C, Hinton DR, Valentin-Torres A, Chen Z, Trapp BD, Bergmann CC, et al. Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis. J Neuroinflammation 2015;12:79.  Back to cited text no. 20
    
21.
Brambilla R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol 2019;137:757-83.  Back to cited text no. 21
    
22.
Hur EM, Zhou FQ. GSK3 signalling in neural development. Nat Rev Neurosci 2010;11:539-51.  Back to cited text no. 22
    
23.
Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 1998;357:299-309.  Back to cited text no. 23
    
24.
Eldar-Finkelman H. Glycogen synthase kinase 3: An emerging therapeutic target. Trends Mol Med 2002;8:126-32.  Back to cited text no. 24
    
25.
Saeki K, Machida M, Kinoshita Y, Takasawa R, Tanuma S. Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1. Biol Pharm Bull 2011;34:146-9.  Back to cited text no. 25
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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