Lab Anim Res.  2011 Dec;27(4):293-299. 10.5625/lar.2011.27.4.293.

Peroxiredoxin I regulates the component expression of gamma-secretase complex causing the Alzheimer's disease

Affiliations
  • 1Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University, Miryang, Korea. dyhwang@pusan.ac.kr
  • 2School of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul, Korea.

Abstract

Peroxiredoxin I (Prx I) is a member of the peroxiredoxins (Prxs) family, which are antioxidant enzymes that regulate various cellular process via intracellular oxidative signal pathways. In order to investigate the correlation between Prx I and the gamma-secretase complex, which causes Alzheimer's disease (AD), the expression level of Prx I was firstly evaluated in an animal model for AD. NSE/hPen-2 transgenic (Tg) mice, which were used as animal model in this study, showed a high level of Pen-2 expression and accumulation of Abeta-42 peptides in the hippocampus of brain. The expression level of Prx I was significantly higher on the mRNA and protein level in the brain of this model, while not change in Prx VI expression was observed. Furthermore, to verify the effect of Prx I on the gamma-secretase components in vitro, the expression level of these components was analyzed in the Prx I transfectants. Of the components of the gamma-secretase complex, the expression of PS-2 and Pen-2 was lower in the transfectants overexpressing Prx I compared to the vector transfectants. However, the expression of APP, NCT and APH-1 did not change in Prx I transfectants. Therefore, these results suggested that the expression of Prx I may be induced by the accumulation of Abeta-42 peptides and the overexpression of Prx I in neuroblastoma cells may regulate the expression of gamma-secretase components.

Keyword

Peroxiredoxin I; gamma-secretase complex; Alzheimer's disease; Abeta-42 peptides

MeSH Terms

Alzheimer Disease
Amyloid Precursor Protein Secretases
Animals
Brain
Hippocampus
Humans
Mice
Models, Animal
Neuroblastoma
Peptides
Peroxiredoxins
RNA, Messenger
Signal Transduction
Amyloid Precursor Protein Secretases
Peptides
Peroxiredoxins
RNA, Messenger

Figure

  • Figure 1 Pen-2 expression and accumulation of Aβ-42 peptides in the brain of CMV/hPen-2 Tg mice. (A) Brain specific expression of the hPen-2 transgenes in the Tg mice by RT-PCR. The β-actin signal was used as the control, and the transcript (640-bp) indicates RNA loading. In addition, the RT-PCR products for hPen-2 (284-bp) are indicated. The density of the amplified transcripts was quantified. (B) Immunostaining analysis of the Aβ-42 peptides. The brains were taken from NSE/hPen-2 Tg mice and Non-Tg mice after perfusion. The level of the Aβ-42 peptide was detected in the immunostaining analysis using an Aβ-42 specific antibody. A high intensity was observed in the hippocampus of the NSE/hPen-2 Tg mice when compared with the Non-Tg mice at 200× magnification. The data represents the mean±SD from three replicates. *P<0.05; significant difference between NSE/hPen-2 Tg and Non-Tg mice.

  • Figure 2 Expression of Prx I and VI mRNA and protein in the brain of NSE/hPen-2 Tg and Non-Tg mice. (A and B) Total RNA was purified from the whole brain of both mice, and the gene expression of the Prx I and VI were detected by RT-PCR. The β-actin signal was used as the control, and the transcript (640-bp) indicates the RNA loading. (C and D) Total tissue lysates were prepared from the brain tissue of NSE/hPen-2 Tg and Non-Tg mice as described in the Materials and Methods sections. Fifty micrograms of protein per sample were immunoblotted using antibodies for each protein. Three samples were assayed in triplicate via Western blotting. The values are expressed as the means±SD. *P<0.05; significant difference between NSE/hPen-2 Tg and Non-Tg mice.

  • Figure 3 Effects of the overexpression of Prx I on the component expression of γ-secretase complex in SH-SY5Y cells. (A) Construction of CMV/hPrx I plasmid. The pCMV/hPrx I harbors the cDNA encoding hPrx I under the control of the CMV gene promoter. (B and C) Total cell lysates were prepared from SH-SY5Y cells transfected with CMV control vector and CMV/hPrx I vector as described in the Materials and Methods section. Fifty micrograms of protein per sample were immunoblotted using antibodies for each protein. Three samples were assayed in triplicate via Western blotting. The values were expressed as means±SD. *P<0.05 is the significance level compared to the vehicle-treated group.


Reference

1. Hoidal JR. Reactive oxygen species and cell signaling. Am J Respir Cell Mol Biol. 2001; 25(6):661–663. PMID: 11726388.
Article
2. Luo Y, Pang H, Li S, Cao H, Peng Z, Fan C, Li S. Production and radioimmunoimaging of novel fully human phage display recombinant antibodies and growth inhibition of lung adenocarcinoma cell line overexpressing Prx I. Cancer Biol Ther. 2009; 8(14):1369–1377. PMID: 19556853.
Article
3. Chae HZ, Kang SW, Rhee SG. Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol. 1999; 300:219–226. PMID: 9919524.
Article
4. Seo MS, Kang SW, Kim K, Baines IC, Lee TH, Rhee SG. Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate. J Biol Chem. 2000; 275(27):20346–20354. PMID: 10751410.
Article
5. Kang SW, Chae HZ, Seo MS, Kim K, Baines IC, Rhee SG. Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-α. J Biol Chem. 1998; 273(11):6297–6302. PMID: 9497357.
Article
6. Okado-Matsumoto A, Matsumoto A, Fujii J, Taniguchi N. Peroxiredoxin IV is a secretable protein with heparin-binding properties under reduced conditions. J Biochem. 2000; 127(3):493–501. PMID: 10731722.
Article
7. Krapfenbauer K, Engidawork E, Cairns N, Fountoulakis M, Lubec G. Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders. Brain Res. 2003; 967(1-2):152–160. PMID: 12650976.
Article
8. Cumming RC, Dargusch R, Fischer WH, Schubert D. Increase in expression levels and resistance to sulfhydryl oxidation of peroxiredoxin isoforms in amyloid beta-resistant nerve cells. J Biol Chem. 2007; 282(42):30523–30534. PMID: 17761673.
9. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature. 2000; 407(6800):48–54. PMID: 10993067.
10. Li YM. Gamma-secretase: a catalyst of Alzheimer disease and signal transduction. Mol Interv. 2001; 1(4):198–207. PMID: 14993342.
11. Nam SH, Seo SJ, Goo JS, Kim JE, Choi SI, Lee HR, Hwang IS, Jee SW, Lee SH, Bae CJ, Park JY, Kim HS, Shim SB, Hwang DY. Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice. Int J Mol Med. 2011; 28:961–971. PMID: 21822534.
Article
12. Hwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, Goo JS, Lee MR, Lim HJ, Min SH, Cho JY, Hong JT, Song CW, Paik SG, Cho JS, Kim YK. Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J. 2002; 16:805–813. PMID: 12039862.
13. Prajapati KD, Sharma SS, Roy N. Upregulation of albumin expression in focal ischemic rat brain. Brain Res. 2010; 1327:118–124. PMID: 20193666.
Article
14. Kim HJ, Chae HZ, Kim YJ, Kim YH, Hwangs TS, Park EM, Park YM. Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues. Cell Biol Toxicol. 2003; 19(5):285–298. PMID: 14703116.
Article
15. Chang JW, Lee SH, Jeong JY, Chae HZ, Kim YC, Park ZY, Yoo YJ. Peroxiredoxin-I is an autoimmunogenic tumor antigen in non-small cell lung cancer. FEBS Lett. 2005; 579(13):2873–2877. PMID: 15876430.
Article
16. Nonn L, Berggren M, Powis G. Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. Mol Cancer Res. 2003; 1(9):682–689. PMID: 12861054.
17. Oda A, Tamaoka A, Araki W. Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells. J Neurosci Res. 2010; 88(5):1137–1145. PMID: 19885829.
Article
18. Yao J, Taylor M, Davey F, Ren Y, Aiton J, Coote P, Fang F, Chen JX, Yan SD, Gunn-Moore FJ. Interaction of amyloid binding alcohol dehydrogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Alzheimer's disease patients and a transgenic Alzheimer's disease mouse model. Mol Cell Neurosci. 2007; 35(2):377–382. PMID: 17490890.
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