MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

Chen,Fang‑Zhou; Zhao,Ying; Chen,Hui‑Zhao

doi:10.3892/ijmm.2018.3957

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

Authors:
- Fang‑Zhou Chen
- Ying Zhao
- Hui‑Zhao Chen
View Affiliations

Affiliations: Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China, Department of Ophthalmology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
Published online on: October 24, 2018 https://doi.org/10.3892/ijmm.2018.3957
Pages: 91-102
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Alzheimer's disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for disease treatment. The aim of the present study was to investigate the effect of miR‑98 on amyloid β (Aβ)‑protein production, oxidative stress and mitochondrial dysfunction through the Notch signaling pathway by targeting hairy and enhancer of split (Hes)‑related with YRPW motif protein 2 (HEY2) in mice with AD. A total of 70 Kunming mice were obtained and subjected to behavioral assessment. The levels of oxidative stress‑related proteins glutathione peroxidase, reduced glutathione, superoxide dismutase, malondialdehyde, acetylcholinesterase and Na+‑K+‑ATP were measured. Morphological changes in brain tissue, HEY2‑positivity levels, neuronal apoptotic index (AI) and neuron mitochondrial DNA (mtDNA) levels were also determined. Subsequently, the levels of miR‑98 and the mRNA and protein levels of HEY2, Jagged1, Notch1, Hes1, Hes5, β‑amyloid precursor protein, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein in tissues and hippocampal neurons were determined by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. Finally, hippocampal neuron viability and apoptosis were determined using an MTT assay and flow cytometry, respectively. The levels of miR‑98‑targeted HEY2 and miR‑98 were low and the levels of HEY2 were high in the AD mice. The AD mice exhibited poorer learning and memory abilities, oxidative stress function, and morphological changes of pyramidal cells in the hippocampal CA1 region. Furthermore, the AD mice exhibited increased protein levels of HEY2 and AI in the CA1 region of brain tissues with reduced mtDNA levels and dysfunctional neuronal mitochondria. miR‑98 suppressed hippocampal neuron apoptosis and promoted hippocampal neuron viability by inactivating the Notch signaling pathway via the inhibition of HEY2. In conclusion, the results demonstrated that miR‑98 reduced the production of Aβ and improved oxidative stress and mitochondrial dysfunction through activation of the Notch signaling pathway by binding to HEY2 in AD mice.

View Figures

View References

1	Wenk GL: Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry. 64(Suppl 9): S7–S10. 2003.
2	Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S and Van der Flier WM: Alzheimer’s disease. Lancet. 388:505–517. 2016. View Article : Google Scholar : PubMed/NCBI
3	Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D and Campos-Peña V: Oxidative stress and metabolic syndrome: Cause or consequence of Alzheimer’s disease. Oxid Med Cell Longev 2014. 497802:2014.
4	Chami L and Checler F: BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease. Mol Neurodegener. 7:522012. View Article : Google Scholar
5	Liggins C, Snyder HM, Silverberg N, Petanceska S, Refolo LM, Ryan L and Carrillo MC: International Alzheimer’s Disease Research Portfolio (IADRP) aims to capture global Alzheimer’s disease research funding. Alzheimers Dement. 10:405–408. 2014. View Article : Google Scholar : PubMed/NCBI
6	Yang Q, Wang T, Su N, Liu Y, Xiao S and Kapoula Z: Long latency and high variability in accuracy-speed of prosaccades in Alzheimer’s disease at mild to moderate stage. Dement Geriatr Cogn Dis Extra. 1:318–329. 2011. View Article : Google Scholar : PubMed/NCBI
7	Sagy-Bross C, Kasianov K, Solomonov Y, Braiman A, Friedman A, Hadad N and Levy R: The role of cytosolic phospholipase A2 α in amyloid precursor protein induction by amyloid beta1-42: Implication for neurodegeneration. J Neurochem. 132:559–571. 2015. View Article : Google Scholar
8	Banote RK, Edling M, Eliassen F, Kettunen P, Zetterberg H and Abramsson A: β-Amyloid precursor protein-b is essential for Mauthner cell development in the zebrafish in a Notch-dependent manner. Dev Biol. 413:26–38. 2016. View Article : Google Scholar : PubMed/NCBI
9	Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, Masliah E and Xu H: Alzheimer’s β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. J Neurosci. 32:11390–11395. 2012. View Article : Google Scholar : PubMed/NCBI
10	Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC and Tycko R: Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell. 154:1257–1268. 2013. View Article : Google Scholar : PubMed/NCBI
11	Bao XQ, Li N, Wang T, Kong XC, Tai WJ, Sun H and Zhang D: FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer’s disease via decreasing beta-amyloid production and tau hyperphosphorylation. PLoS One. 8:e780332013. View Article : Google Scholar
12	Jiang Y, Zhou Z, Meng QT, Sun Q, Su W, Lei S, Xia Z and Xia ZY: Ginsenoside Rb1 treatment attenuates pulmonary inflammatory cytokine release and tissue injury following intestinal ischemia reperfusion injury in mice. Oxid Med Cell Longev. 2015.843721:2015.
13	Simonian NA and Coyle JT: Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 36:83–106. 1996. View Article : Google Scholar : PubMed/NCBI
14	Muhammad S, Bierhaus A and Schwaninger M: Reactive oxygen species in diabetes-induced vascular damage, stroke, and Alzheimer’s disease. J Alzheimers Dis. 16:775–785. 2009. View Article : Google Scholar
15	Shen GX: Mitochondrial dysfunction, oxidative stress and diabetic cardiovascular disorders. Cardiovasc Hematol Disord Drug Targets. 12:106–112. 2012. View Article : Google Scholar : PubMed/NCBI
16	Li X, Zhang M and Zhou H: The morphological features and mitochondrial oxidative stress mechanism of the retinal neurons apoptosis in early diabetic rats. J Diabetes Res. 2014.678123:2014.
17	Weir HJ, Murray TK, Kehoe PG, Love S, Verdin EM, O’Neill MJ, Lane JD and Balthasar N: CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer’s disease. PLoS One. 7:e482252012. View Article : Google Scholar
18	Wang X, Wang W, Li L, Perry G, Lee HG and Zhu X: Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 1842.1240–1247. 2014.
19	Brunst KJ, Sanchez Guerra M, Gennings C, Hacker M, Jara C, Bosquet Enlow M, Wright RO, Baccarelli A and Wright RJ: Maternal lifetime stress and prenatal psychological functioning are associated with decreased placental mitochondrial DNA copy number in the PRISM study. Am J Epidemiol. 186:1227–1236. 2017. View Article : Google Scholar : PubMed/NCBI
20	Hayashi Y, Haneji N, Hamano H and Yanagi K: Transfer of Sjogren’s syndrome-like autoimmune lesions into SCID mice and prevention of lesions by anti-CD4 and anti-T cell receptor antibody treatment. Eur J Immunol. 24:2826–2831. 1994. View Article : Google Scholar : PubMed/NCBI
21	Wu DC, Zhang MF, Su SG, Fang HY, Wang XH, He D, Xie YY and Liu XH: HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget. 7:38052–38063. 2016.PubMed/NCBI
22	Morioka T, Sakabe M, Ioka T, Iguchi T, Mizuta K, Hattammaru M, Sakai C, Itoh M, Sato GE, Hashimoto A, et al: An important role of endothelial hairy-related transcription factors in mouse vascular development. Genesis. 52:897–906. 2014. View Article : Google Scholar : PubMed/NCBI
23	Vidigal JA and Ventura A: The biological functions of miRNAs: Lessons from in vivo studies. Trends Cell Biol. 25:137–147. 2015. View Article : Google Scholar :
24	Siragam V, Rutnam ZJ, Yang W, Fang L, Luo L, Yang X, Li M, Deng Z, Qian J, Peng C and Yang BB: MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11. Oncotarget. 3:1370–1385. 2012. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Cummings J, Lee G, Mortsdorf T, Ritter A and Zhong K: Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (NY). 3:367–384. 2017.
27	Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, et al: Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 546:5642017. View Article : Google Scholar
28	Kocahan S and Doğan Z: Mechanisms of Alzheimer’s disease pathogenesis and prevention: The brain, neural pathology, N-methyl-D-aspartate receptors, tau protein and other risk factors. Clin Psychopharmacol Neurosci. 15:1–8. 2017. View Article : Google Scholar : PubMed/NCBI
29	Saed GM, Diamond MP and Fletcher NM: Updates of the role of oxidative stress in the pathogenesis of ovarian cancer. Gynecol Oncol. 145:595–602. 2017. View Article : Google Scholar : PubMed/NCBI
30	Yang EJ, Ahn S, Ryu J, Choi MS, Choi S, Chong YH, Hyun JW, Chang MJ and Kim HS: Phloroglucinol attenuates the cognitive deficits of the 5XFAD mouse model of Alzheimer’s disease. PLoS One. 10:e01356862015. View Article : Google Scholar
31	Moslemnezhad A, Mahjoub S and Moghadasi M: Altered plasma marker of oxidative DNA damage and total antioxidant capacity in patients with Alzheimer’s disease. Caspian J Intern Med. 7:88–92. 2016.PubMed/NCBI
32	Malik AN and Czajka A: Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction. Mitochondrion. 13:481–492. 2013. View Article : Google Scholar
33	Banerjee A and Luettich K: MicroRNAs as potential biomarkers of smoking-related diseases. Biomark Med. 6:671–684. 2012. View Article : Google Scholar : PubMed/NCBI
34	Panda H, Chuang TD, Luo X and Chegini N: Endometrial miR-181a and miR-98 expression is altered during transition from normal into cancerous state and target PGR, PGRMC1, CYP19A1, DDX3X, and TIMP3. J Clin Endocrinol Metab. 97:E1316–E1326. 2012. View Article : Google Scholar : PubMed/NCBI
35	Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T and Tan L: Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer’s disease. J Alzheimers Dis. 40:1017–1027. 2014. View Article : Google Scholar
36	Li Q, Li X, Wang L, Zhang Y and Chen L: miR-98-5p acts as a target for Alzheimer’s disease by regulating Aβ production through modulating SNX6 expression. J Mol Neurosci. 60:413–420. 2016. View Article : Google Scholar : PubMed/NCBI
37	Hu YK, Wang X, Li L, Du YH, Ye HT and Li CY: MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1. Neurosci Bull. 29:745–751. 2013. View Article : Google Scholar : PubMed/NCBI
38	Liu QY, Chang MN, Lei JX, Koukiekolo R, Smith B, Zhang D and Ghribi O: Identification of microRNAs involved in Alzheimer’s progression using a rabbit model of the disease. Am J Neurodegener Dis. 3:33–44. 2014.
39	Marathe S, Jaquet M, Annoni JM and Alberi L: Jagged1 is altered in Alzheimer’s disease and regulates spatial memory processing. Front Cell Neurosci. 11:2202017. View Article : Google Scholar
40	Brai E, Alina Raio N and Alberi L: Notch1 hallmarks fibrillary depositions in sporadic Alzheimer’s disease. Acta Neuropathol Commun. 4:642016. View Article : Google Scholar
41	Kageyama R, Shimojo H and Imayoshi I: Dynamic expression and roles of Hes factors in neural development. Cell Tissue Res. 359:125–133. 2015. View Article : Google Scholar
42	Dawkins E and Small DH: Insights into the physiological function of the β-amyloid precursor protein: Beyond Alzheimer’s disease. J Neurochem. 129:756–769. 2014. View Article : Google Scholar : PubMed/NCBI
43	MacGibbon GA, Lawlor PA, Sirimanne ES, Walton MR, Connor B, Young D, Williams C, Gluckman P, Faull RL, Hughes P and Dragunow M: Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer’s disease hippo-campus. Brain Res. 750:223–234. 1997. View Article : Google Scholar : PubMed/NCBI
44	Burghardt NS, Park EH, Hen R and Fenton AA: Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus. 22:1795–1808. 2012. View Article : Google Scholar : PubMed/NCBI
45	Wang J, Chen L, Jin S, Lin J, Zheng H, Zhang H, Fan H, He F, Ma S and Li Q: Altered expression of microRNA-98 in IL-1β-induced cartilage degradation and its role in chondrocyte apoptosis. Mol Med Rep. 16:3208–3216. 2017. View Article : Google Scholar : PubMed/NCBI
46	Lannfelt L, Relkin NR and Siemers ER: Amyloid-β-directed immunotherapy for Alzheimer’s disease. J Intern Med. 275:284–295. 2014. View Article : Google Scholar : PubMed/NCBI