Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells

Guo,Peng; Wang,Desheng; Wang,Xiaomin; Feng,Honglin; Tang,Ying; Sun,Ruihong; Zheng,Yan; Dong,Lin; Zhao,Jiaying; Zhang,Xin; Wang,Shuyu; Sun,Hongxu

doi:10.3892/mmr.2016.4957

Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells

Authors:
- Peng Guo
- Desheng Wang
- Xiaomin Wang
- Honglin Feng
- Ying Tang
- Ruihong Sun
- Yan Zheng
- Lin Dong
- Jiaying Zhao
- Xin Zhang
- Shuyu Wang
- Hongxu Sun
View Affiliations

Affiliations: Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, P.R. China
Published online on: March 1, 2016 https://doi.org/10.3892/mmr.2016.4957
Pages: 3539-3546

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to determine the effect and mechanism of fuzhisan (FZS) and donepezil on the SIRT1 signaling pathway and the metabolism of the amyloid precursor protein (APP) in PC12 cells. An experimental cell model of PC12 cells with Aβ25‑35‑induced neurotoxicity was established and cell proliferation was determined by the MTT assay following treatment with donepezil and FZS. In addition, cell apoptosis was determined using DAPI staining and light microscopy. Furthermore, western blot analysis and ELISA were utilized to evaluate the expression levels of associated APP, Aβ40, Aβ42, sAPPα, sAPPβ, ADAM10, sirtuin 1 (SIRT1) and forkhead box O (FoxO) protein. The results indicated that the cell model was successfully established and FZS protected the PC12 cells from the neurotoxic effects of Aβ25‑35, in a similar effect to donepezil, in a dose‑dependent manner. The expression of APP remained at the same level during the experimental period. The levels of Aβ40, Aβ42 and sAPPβ were downregulated, where as sAPPα, ADAM10, SIRT1 and FoxO expression levels were upregulated. In conclusion, FZS treatment attenuated the Aβ25‑35‑induced neurotoxicity in vitro. The neuroprotective mechanism of FZS was determined, including the induction of ADAM10 and SIRT1‑FoxO pathway, which participated in the process of neuroprotection. The present study identified the neuroprotective function of FZS, which may protect against Aβ‑induced toxicity. Therefore, FZS may be used clinically as a beneficial therapeutic drug for the development or progression of Alzheimer's disease.

View Figures

View References

1	Xing S, Shen D, Chen C, Wang J and Yu Z: Early induction of oxidative stress in a mouse model of Alzheimer's disease with heme oxygenase activity. Mol Med Rep. 10:599–604. 2014.PubMed/NCBI
2	Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, et al Alzheimer's Disease International: Global prevalence of dementia: A Delphi consensus study. Lancet. 366:2112–2117. 2005. View Article : Google Scholar : PubMed/NCBI
3	Walsh DM and Selkoe DJ: Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron. 44:181–193. 2004. View Article : Google Scholar : PubMed/NCBI
4	Hardy J and Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science. 297:353–356. 2002. View Article : Google Scholar : PubMed/NCBI
5	Tanzi RE and Bertram L: Twenty years of the Alzheimer's disease amyloid hypothesis: A genetic perspective. Cell. 120:545–555. 2005. View Article : Google Scholar : PubMed/NCBI
6	Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, et al: A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer's disease mouse model. J Clin Invest. 113:1456–1464. 2004. View Article : Google Scholar : PubMed/NCBI
7	De Strooper B: Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 8:141–146. 2007. View Article : Google Scholar : PubMed/NCBI
8	Kojro E and Fahrenholz F: The non-amyloidogenic pathway: Structure and function of α-secretases. Subcell Biochem. 38:105–127. 2005. View Article : Google Scholar
9	Sinclair DA and Guarente L: Extrachromosomal rDNA circles - a cause of aging in yeast. Cell. 91:1033–1042. 1997. View Article : Google Scholar
10	Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L and Gan L: SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 280:40364–40374. 2005. View Article : Google Scholar : PubMed/NCBI
11	Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, et al: Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 281:21745–21754. 2006. View Article : Google Scholar : PubMed/NCBI
12	Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, et al: SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26:3169–3179. 2007. View Article : Google Scholar : PubMed/NCBI
13	Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA and Calon F: Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 68:48–58. 2009. View Article : Google Scholar
14	Donmez G and Guarente L: Aging and disease: Connections to sirtuins. Aging Cell. 9:285–290. 2010. View Article : Google Scholar : PubMed/NCBI
15	Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, et al: Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 67:953–966. 2010. View Article : Google Scholar : PubMed/NCBI
16	Donmez G: The neurobiology of sirtuins and their role in neurodegeneration. Trends Pharmacol Sci. 33:494–501. 2012. View Article : Google Scholar : PubMed/NCBI
17	Donmez G, Wang D, Cohen DE and Guarente L: SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 142:320–332. 2010. View Article : Google Scholar : PubMed/NCBI
18	Haigis MC and Sinclair DA: Mammalian sirtuins: Biological insights and disease relevance. Annu Rev Pathol. 5:253–295. 2010. View Article : Google Scholar : PubMed/NCBI
19	Li XL, Wang S, Zhao BQ, Li Q, Qu HY, Zhang T, Zhou JP and Sun MJ: Effects of Chinese herbal medicine fuzhisan on aged rats. Exp Gerontol. 43:853–858. 2008. View Article : Google Scholar : PubMed/NCBI
20	Zhao J, Wang D, Duan S, Wang J, Bai J and Li W: Analysis of fuzhisan and quantitation of baicalin and ginsenoside Rb(1) by HPLC-DAD-ELSD. Arch Pharm Res. 32:989–996. 2009. View Article : Google Scholar : PubMed/NCBI
21	Gang BZ and Wang CL: The efficacy of Fuzhisan in patients with Alzheimer's disease. Chin J Apoplexy Nerv Dis. 22:527–529. 2005.
22	Wen SR, Wang DS and Zhang JY: Effect of Fuzhisan on the area of neurosome and the length of axon. Chin J Clin Rehabil. 9:241–243. 2005.
23	Shirong W, Desheng W and Jingyan Z: The effect of FZS on the cellular function of SH-SY5Y. J Harbin Med Univ. 37:383–388. 2003.
24	Sul D, Kim HS, Lee D, Joo SS, Hwang KW and Park SY: Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation. Life Sci. 84:257–262. 2009. View Article : Google Scholar
25	Hartmann D, Tournoy J, Saftig P, Annaert W and De Strooper B: Implication of APP secretases in notch signaling. J Mol Neurosci. 17:171–181. 2001. View Article : Google Scholar
26	Vieira SI, Rebelo S and Domingues SC: da Cruz e Silva EF and da Cruz e Silva OA. S655 phosphorylation enhances APP secretory traffic. Mol Cell Biochem. 9:8–17. 2009.
27	Goodman AB: Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. J Cell Physiol. 209:598–603. 2006. View Article : Google Scholar : PubMed/NCBI
28	Costa RM, Drew C and Silva AJ: Notch to remember. Trends Neurosci. 28:429–435. 2005. View Article : Google Scholar : PubMed/NCBI
29	Corcoran JPT, So PL and Maden M: Disruption of the retinoid signalling pathway causes a deposition of amyloid β in the adult rat brain. Eur J Neurosci. 20:896–902. 2004. View Article : Google Scholar : PubMed/NCBI
30	Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, et al: The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 3:e20202008. View Article : Google Scholar : PubMed/NCBI
31	Yoon K and Gaiano N: Notch signaling in the mammalian central nervous system: Insights from mouse mutants. Nat Neurosci. 8:709–715. 2005. View Article : Google Scholar : PubMed/NCBI
32	Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE and Finch CE: Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. 26:995–1000. 2005. View Article : Google Scholar : PubMed/NCBI
33	Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, et al: Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci. 31:2511–2525. 2011. View Article : Google Scholar : PubMed/NCBI
34	Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, et al: Tau suppression in a neurodegenerative mouse model improves memory function. Science. 309:476–481. 2005. View Article : Google Scholar : PubMed/NCBI
35	Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA and Calon F: Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 68:48–58. 2009. View Article : Google Scholar
36	Frescas D, Valenti L and Accili D: Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem. 280:20589–20595. 2005. View Article : Google Scholar : PubMed/NCBI
37	Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, et al: Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 303:2011–2015. 2004. View Article : Google Scholar : PubMed/NCBI
38	Giannakou ME and Partridge L: The interaction between FOXO and SIRT1: Tipping the balance towards survival. Trends Cell Biol. 14:408–412. 2004. View Article : Google Scholar : PubMed/NCBI
39	Chen X, Huang T, Zhang J, Song J, Chen L and Zhu Y: Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1's attenuation of beta-amyloid peptide25–35-induced tau hyperphosphorylation in cortical neurons. Brain Res. 1200:99–106. 2008. View Article : Google Scholar : PubMed/NCBI
40	Lee CH, Kim JM, Kim DH, Park SJ, Liu X, Cai M, Hong JG, Park JH and Ryu JH: Effects of Sun ginseng on memory enhancement and hippocampal neurogenesis. Phytother Res. 27:1293–1299. 2013. View Article : Google Scholar