Genistein Decreases APP/tau Phosphorylation and Ameliorates Aβ Overproduction Through Inhibiting CIP2A

Author(s): Yang-Ping Shentu*, Wen-Ting Hu, Jia-Wei Liang, Zhen-Yu Liuyang, Hui Wei, Wang Qun, Xiao-Chuan Wang, Jian-Zhi Wang, Jukka Westermarck, Rong Liu*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 8 , 2019

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Background: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease-related phosphorylation of tau/APP and tau pathology/Aβ overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation.

Methods: The inhibitory effects of Genistein on tau/APP phosphorylation and Aβ overproduction in AD cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668, total APP, PS1, BACE1, sAPPα and sAPPβ. Aβ40 and Aβ42 levels in cell supernatant, soluble fraction (RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau.

Results: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aβ production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing the inhibitory effect of CIP2A on PP2A.

Conclusion: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation and Aβ production through inhibiting the effect of CIP2A on PP2A.

Keywords: CIP2A, Genistein, tau, APP β-cleavage, Alzheimer disease, neurofibrillary.

Braak H, Braak E. The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases. Neurosci Res 15(1-2): 6-31. 1992
[] [PMID: 1336586]
Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, et al. CIP2A inhibits PP2A in human malignancies. Cell 130(1): 51-62. 2007
[] [PMID: 17632056]
Soo Hoo L, Zhang JY, Chan EK. Cloning and characterization of a novel 90 kDa ‘companion’ auto-antigen of p62 overexpressed in cancer Oncogene 2002; 21(32): 5006-15 2002
[] [PMID: 12118381]
Khanna A, Pimanda JE, Westermarck J. Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target. Cancer Res 73(22): 6548-53. 2013
[] [PMID: 24204027]
Zhang Y, Fang L, Zang Y, Ren J, Xu Z. CIP2A promotes proliferation, invasion and chemoresistance to cisplatin in renal cell carcinoma. J Cancer 9(21): 4029-38. 2018
[] [PMID: 30410608]
Kerosuo L, Fox H, Perälä N, Ahlqvist K, Suomalainen A, Westermarck J, et al. CIP2A increases self-renewal and is linked to Myc in neural progenitor cells. Differentiation 80(1): 68-77. 2010
[] [PMID: 20447748]
Shentu YP, Huo Y, Feng XL, Gilbert J, Zhang Q, Liuyang ZY, et al. CIP2A causes Tau/APP phosphorylation, synaptopathy and memory deficits in Alzheimer’s disease. Cell Rep 24(3): 713-23. 2018
[] [PMID: 30021167]
Devi KP, Shanmuganathan B, Manayi A, Nabavi SF, Nabavi SM. Molecular and therapeutic targets of genistein in Alzheimer’s disease. Mol Neurobiol 54(9): 7028-41. 2017
[] [PMID: 27796744]
Zhao Q, Zhao M, Parris AB, Xing Y, Yang X. Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells. Int J Oncol 49(3): 1203-10. 2016
[] [PMID: 27574003]
Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12(1): 15-27. 2016
[] [PMID: 26635213]
Sontag E, Nunbhakdi-Craig V, Sontag JM, Diaz-Arrastia R, Ogris E, Dayal S, et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci 27(11): 2751-9. 2007
[] [PMID: 17360897]
Dennis MD, Coleman CS, Berg A, Jefferson LS, Kimball SR. REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling. Sci Signal 7(335): ra68. 2014
[] [PMID: 25056877]
Ugi S, Imamura T, Ricketts W, Olefsky JM. Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. Mol Cell Biol 22(7): 2375-87. 2002
[] [PMID: 11884620]
Wang J, Okkeri J, Pavic K, Wang Z, Kauko O, Halonen T, et al. Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56. EMBO Rep 18(3): 437-50. 2017
[] [PMID: 28174209]
Xue Y, Wu G, Wang X, Zou X, Zhang G, Xiao R, et al. CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma. Med Oncol 30(1): 406-17. 2013
[] [PMID: 23275123]
De P, Carlson J, Leyland-Jones B, Dey N. Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): an oncoprotein with many hands. Oncotarget 5(13): 4581-602. 2014
[] [PMID: 25015035]
Amiri Gheshlaghi S, Mohammad Jafari R, Algazo M, Rahimi N, Alshaib H, Dehpour AR. Genistein modulation of seizure: involvement of estrogen and serotonin receptors. J Nat Med 71(3): 537-44. 2017
[] [PMID: 28439683]
Spagnuolo C, Russo GL, Orhan IE, Habtemariam S, Daglia M, Sureda A, et al. Genistein and cancer: current status, challenges, and future directions Adv Nutr 6: 08-19 2015
Banerjee S, Li Y, Wang Z, Sarkar FH. Multi-targeted therapy of cancer by genistein. Cancer Lett 269(2): 226-42. 2008
[] [PMID: 18492603]
Vanden Braber NL, Novotny Nuñez I, Bohl L, et al. Soy genistein administered in soluble chitosan microcapsules maintains antioxidant activity and limits intestinal inflammation. J Nutr Biochem 2018; 62: 50-8.
[] [PMID: 30245183]
Bagheri M, Joghataei MT, Mohseni S, Roghani M. Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer’s disease. Neurobiol Learn Mem 95(3): 270-6. 2011
[] [PMID: 21144907]
Wang Y, Cai B, Shao J, Wang TT, Cai RZ, Ma CJ, et al. Genistein suppresses the mitochondrial apoptotic pathway in hippocampal neurons in rats with Alzheimer’s disease. Neural Regen Res 11(7): 1153-8. 2016
[] [PMID: 27630702]
Ren B, Liu Y, Zhang Y, Cai Y, Gong X, Chang Y, et al. Genistein: a dual inhibitor of both amyloid β and human islet amylin peptides. ACS Chem Neurosci 9(5): 1215-24. 2018
[] [PMID: 29432676]
Park YJ, Ko JW, Jeon S, Kwon YH. Protective effect of genistein against neuronal degeneration in ApoE-/- mice fed a high-fat diet. Nutrients 8(11): 692-703. 2016
[] [PMID: 27809235]
Youn K, Park JH, Lee S, Lee S, Lee J, Yun EY, et al. BACE1 inhibition by genistein: biological evaluation, kinetic analysis, and molecular docking simulation. J Med Food 21(4): 416-20. 2018
[] [PMID: 29444415]

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Article Details

Year: 2019
Published on: 10 October, 2019
Page: [732 - 740]
Pages: 9
DOI: 10.2174/1567205016666190830113420
Price: $65

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