Volume 9, Issue 4 (Vol.9 No.4 Jan 2021)                   rbmb.net 2021, 9(4): 417-425 | Back to browse issues page

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Chan H H, Leong Y Q, Voon S M, Pan M L, Leong C O, Lim C L et al . Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells. rbmb.net 2021; 9 (4) :417-425
URL: http://rbmb.net/article-1-509-en.html
Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells
Hong Hao Chan , Yong Qi Leong , Shee Man Voon , Meng Liy Pan , Chee Onn Leong , Chooi Ling Lim , Rhun Yian Koh *
Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia.
Abstract:   (3704 Views)
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that causes cognitive dysfunction. Previous studies have suggested that amyloid plaques, mainly comprising of amyloid-beta peptides, play a pivotal role in AD pathophysiology. This study focuses on the evaluation of the effects of amyloid precursor protein (APP) overexpression on NF-κB, Rho-GTPase and Bcl-2 mediated pro-apoptotic pathways in neuronal cells.

Methods: A lentiviral transduction system was used to generate SH-SY5Y cells overexpressing APP. Immunoblotting was conducted to determine expression levels of NF-κB, Rho-GTPase, and Bcl-2 family proteins in the APP overexpressed cells.

Results: In the NF-κB signaling pathway, APP-overexpressing SH-SY5Y cells showed that there was a reduction of p-NF-κB (p< 0.05) and IKKα. Subsequently, there was upregulation of protein expression of NF-Κb, IKKβ and IκBα. On the other hand, protein expression of RhoC (p< 0.05) and Rac1/2/3 was upregulated as compared to the control group. Meanwhile, a decrease in RhoA, Cdc42 (p< 0.05) and p-Rac1/cdc42 protein levels was observed in the APP-overexpressed group. Lastly, in the pro-apoptotic pathway, the expression of Bcl-2, Bid, Bok and Puma (p< 0.05) was up regulated in the APP-overexpressed group. Downregulation of Bad and Bim expression was observed in the APP-overexpressed as compared to the control group, and Bax expression remained unchanged in the APP-overexpressed group.

Conclusions: APP overexpression regulated signaling in the NF-κB, Rho-GTPase and Bcl-2 family pathways in neuronal cells, suggesting that these are involved in promoting neuronal survival and modulating synaptic plasticity in AD. However, further studies are essential to elucidate the APP-mediated mechanism of action.
 
Keywords: Alzheimer’s disease, Amyloid precursor protein, Bcl-2 family proteins, NF-κB, Rho-GTPase.
Full-Text [PDF 275 kb]   (1425 Downloads)    
Type of Article: Original Article | Subject: Cell Biology
Received: 2020/05/30 | Accepted: 2020/06/8 | Published: 2021/03/8
References
1. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004;430(7000):631-639. [DOI:10.1038/nature02621] [PMID] [PMCID]
2. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33(1):95-130. [DOI:10.1016/S0165-0173(00)00019-9]
3. Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 2013;587(13):2046-54. [DOI:10.1016/j.febslet.2013.05.010] [PMID]
4. Dong S, Duan Y, Hu Y, Zhao Z. Advances in the pathogenesis of Alzheimer's disease: a re-evaluation of amyloid cascade hypothesis. Transl Neurodegener. 2012;1:18. [DOI:10.1186/2047-9158-1-18] [PMID] [PMCID]
5. Alva G, Potkin SG. Alzheimer disease and other dementias. Clinics in geriatric medicine. 2003;19(4):763-776. [DOI:10.1016/S0749-0690(03)00028-4]
6. Selkoe DJ. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci. 1994;17:489-517. [DOI:10.1146/annurev.ne.17.030194.002421] [PMID]
7. Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med. 2010;12(1):1-12. [DOI:10.1007/s12017-009-8104-z] [PMID] [PMCID]
8. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-kappaB in Aging and Disease. Aging Dis. 2011;2(6):449-65.
9. Sun SC, Chang JH, Jin J. Regulation of nuclear factor-kappaB in autoimmunity. Trends Immunol. 2013;34(6):282-9. [DOI:10.1016/j.it.2013.01.004] [PMID] [PMCID]
10. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1(4):a000034. [DOI:10.1101/cshperspect.a000034] [PMID] [PMCID]
11. Hinz M, Scheidereit C. The IkappaB kinase complex in NF-kappaB regulation and beyond. EMBO reports. 2014;15(1):46-61. [DOI:10.1002/embr.201337983] [PMID] [PMCID]
12. Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, et al. Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol. 2012;15(1):77-90. [DOI:10.1017/S1461145711000149] [PMID]
13. Niedernhofer LJ, Robbins PD. Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan. The international journal of biochemistry & cell biology. 2008;40(2):176-180. [DOI:10.1016/j.biocel.2007.10.008] [PMID] [PMCID]
14. Coppe JP, Patil CK, Rodier F, Krtolica A, Beausejour CM, Parrinello S, et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PloS one. 2010;5(2):e9188. [DOI:10.1371/journal.pone.0009188] [PMID] [PMCID]
15. Musilli M, Nicolia V, Borrelli S, Scarpa S, Diana G. Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease. Behavioural brain research. 2013;237:223-229. [DOI:10.1016/j.bbr.2012.09.043] [PMID]
16. Bolognin S, Lorenzetto E, Diana G, Buffelli M. The potential role of rho GTPases in Alzheimer's disease pathogenesis. Mol Neurobiol. 2014;50(2):406-22. [DOI:10.1007/s12035-014-8637-5] [PMID]
17. Boureux A, Vignal E, Faure S, Fort P. Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol. 2007;24(1):203-16. [DOI:10.1093/molbev/msl145] [PMID] [PMCID]
18. Govek EE, Newey SE, Van Aelst L. The role of the Rho GTPases in neuronal development. Genes Dev. 2005;19(1):1-49. [DOI:10.1101/gad.1256405] [PMID]
19. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992;12(2):376-89. [DOI:10.1523/JNEUROSCI.12-02-00376.1992] [PMID] [PMCID]
20. Kanamaru T, Kamimura N, Yokota T, Iuchi K, Nishimaki K, Takami S, et al. Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease. Neuroscience letters. 2015;587:126-131. [DOI:10.1016/j.neulet.2014.12.033] [PMID]
21. Willis S, Day CL, Hinds MG, Huang DC. The Bcl-2-regulated apoptotic pathway. J Cell Sci. 2003;116(Pt 20):4053-6. [DOI:10.1242/jcs.00754] [PMID]
22. Akhtar RS, Ness JM, Roth KA. Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta. 2004;1644(2-3):189-203. [DOI:10.1016/j.bbamcr.2003.10.013] [PMID]
23. Gutierrez H, Hale VA, Dolcet X, Davies A. NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development. 2005;132(7):1713-26. [DOI:10.1242/dev.01702] [PMID]
24. Merlo E, Freudenthal R, Romano A. The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus. Neuroscience. 2002;112(1):161-72. [DOI:10.1016/S0306-4522(02)00049-0]
25. Haenold R, Weih F, Herrmann KH, Schmidt KF, Krempler K, Engelmann C, et al. NF-kappaB controls axonal regeneration and degeneration through cell-specific balance of RelA and p50 in the adult CNS. J Cell Sci. 2014;127(Pt 14):3052-65. [DOI:10.1242/jcs.140731] [PMID]
26. Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem. 2002;277(6):3863-9. [DOI:10.1074/jbc.M110572200] [PMID]
27. Huesa G, Baltrons MA, Gomez-Ramos P, Moran A, Garcia A, Hidalgo J, et al. Altered distribution of RhoA in Alzheimer's disease and AbetaPP overexpressing mice. J Alzheimers Dis. 2010;19(1):37-56. [DOI:10.3233/JAD-2010-1203] [PMID]
28. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, et al. Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Laboratory investigation. 2003;83(6):861-70. [DOI:10.1097/01.LAB.0000073128.16098.31] [PMID]
29. Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, et al. A definitive role of RhoC in metastasis of orthotopic lung cancer in mice. Clin Cancer Res. 2004;10(3):1192-200. [DOI:10.1158/1078-0432.CCR-03-0275] [PMID]
30. Egami Y, Kawai K, Araki N. RhoC regulates the actin remodeling required for phagosome formation during FcgammaR-mediated phagocytosis. Journal of cell science. 2017;130(24):4168-4179. [DOI:10.1242/jcs.202739] [PMID]
31. Watabe-Uchida M, Govek EE, Van Aelst L. Regulators of Rho GTPases in neuronal development. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2006;26(42):10633-5. [DOI:10.1523/JNEUROSCI.4084-06.2006] [PMID] [PMCID]
32. Wennerberg K, Der CJ. Rho-family GTPases: it's not only Rac and Rho (and I like it). Journal of cell science. 2004;117(Pt 8):1301-12. [DOI:10.1242/jcs.01118] [PMID]
33. Threadgill R, Bobb K, Ghosh A. Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron. 1997;19(3):625-634. [DOI:10.1016/S0896-6273(00)80376-1]
34. Luo L, Liao YJ, Jan LY, Jan YN. Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. Genes & development. 1994;8(15):1787-802. [DOI:10.1101/gad.8.15.1787] [PMID]
35. Moreau V, Way M. Cdc42 is required for membrane dependent actin polymerization in vitro. FEBS letters. 1998;427(3):353-356. [DOI:10.1016/S0014-5793(98)00443-8]
36. Ruchhoeft ML, Ohnuma S, McNeill L, Holt CE, Harris WA. The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo. The Journal of neuroscience: the official journal of the Society for Neuroscience. 1999;19(19):8454-63. [DOI:10.1523/JNEUROSCI.19-19-08454.1999] [PMID] [PMCID]
37. Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, et al. p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. The Journal of biological chemistry. 2008;283(20):14132-43. [DOI:10.1074/jbc.M708034200] [PMID] [PMCID]
38. Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nature neuroscience. 2006;9(2):234-42. [DOI:10.1038/nn1630] [PMID]
39. Shen JN, Wang DS, Wang R. The protection of acetylcholinesterase inhibitor on beta-amyloid-induced the injury of neurite outgrowth via regulating axon guidance related genes expression in neuronal cells. International journal of clinical and experimental pathology. 2012;5(9):900-13.
40. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer cell. 2006;9(5):351-365. [DOI:10.1016/j.ccr.2006.03.027] [PMID]
41. Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria. PNAS. 1998;95(9):4997-5002. [DOI:10.1073/pnas.95.9.4997] [PMID] [PMCID]
42. Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, et al. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. PNAS. 1998;95(25):14681-14686. 43. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205-19. [DOI:10.1016/S0092-8674(04)00046-7]
43. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479-89. [DOI:10.1016/S0092-8674(00)80434-1]
44. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405-13. [DOI:10.1016/S0092-8674(00)80501-2]
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