Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Down-Regulation of Mir-107 Worsen Spatial Memory by Suppressing SYK Expression and Inactivating NF-ΚB Signaling Pathway

Author(s): Wenjie Hu, Lin Wen, Fang Cao and Yexin Wang*

Volume 16, Issue 2, 2019

Page: [135 - 145] Pages: 11

DOI: 10.2174/1567205016666181212154347

Price: $65

Abstract

Background: Alzheimer’s Disease (AD) is a chronic progressive neurodegenerative disorder in a central nervous system seen.

Objective: We aimed to study the miR-107 in Alzheimer's Disease (AD) pathology through regulating SYK and NF-κB signaling pathway.

Method: Bioinformatics analysis was performed to screen NF-κB signaling pathway and differentially expressed genes. The target relationship between miR-107 and SYK was verified by dual luciferase assay. QRT-PCR and western blot analysis were used to verify the expression level of miR-107, SYK and NF- κB signaling pathway related proteins of hippocampus primary neurons. BAY61-3606 and BAY11-7082 were purchased for functional examination. Morris water maze tests were performed to access spatial memory of AD mice with SYK and NF-κB signaling pathway inhibition. Fluorescence microscope dyeing experiment investigated the neurons nuclear form and apoptosis.

Results: MiR-107 was lowly expressed while SYK was highly expressed in Tg19959 mouse model. Luciferase Assay confirmed the target relationship in miR-107 and SYK. With the inhibition of miR-107, SYK was up-regulated and the increase of p-p65 and the decrease of p-IκB-α suggested that NF-κB signaling pathway was activated in vitro. Morris water maze test indicated that the spatial memory of Tg19959 mice was increased with the treatment. The result of DAPI staining indicated that the inhibition of SYK or NF-κB signaling pathway reduced the apoptosis of Tg19959 mice neuron cell.

Conclusion: MiR-107 exerts its effects through suppression of the NF-κB signaling pathway and SYK, the inhibition of SYK and NF-κB signaling pathway can improve spatial memory and suppress cell apoptosis.

Keywords: miR-107, SYK, NF-κB, Alzheimer's disease, bioinformatics analysis, cell apoptosis.

[1]
Gregori M, Masserini M, Mancini S. Nanomedicine for the treatment of Alzheimer’s disease. Nanomedicine 10(7): 1203-18. (2015).
[2]
Wang X, Blanchard J, Grundke-Iqbal I, Wegiel J, Deng HX, Siddique T, et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol 127(2): 243-56. (2014).
[3]
Ittner LM, Gotz J. Amyloid-beta and tau--a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12(2): 65-72. (2011).
[4]
Yan R, Vassar R. Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13(3): 319-29. (2014).
[5]
Masterman D. Treatment of the neuropsychiatric symptoms in Alzheimer’s disease. J Am Med Dir Assoc 4(6)(Suppl.): S146-54. (2003).
[6]
Hyun S, Han A, Jo MH, Hohng S, Yu J. Dicer nuclease-promoted production of Let7a-1 microRNA is enhanced in the presence of tryptophan-containing amphiphilic peptides. Chembiochem: A Eur. J Chem Biol 15(11): 1651-9. (2014).
[7]
Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39(Database issue): D152-7. (2011).
[8]
Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19(1): 92-105. (2009).
[9]
Zhu QB, Unmehopa U, Bossers K, Hu YT, Verwer R, Balesar R, et al. MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer’s disease. Brain 139(Pt 3): 908-21. (2016).
[10]
Banzhaf-Strathmann J, Benito E, May S, Arzberger T, Tahirovic S, Kretzschmar H, et al. MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer’s disease. EMBO J 33(15): 1667-80. (2014).
[11]
Augustin R, Endres K, Reinhardt S, Kuhn PH, Lichtenthaler SF, Hansen J, et al. Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med Genet 13: 35. (2012).
[12]
Jiang ZP, Zhou TB. Role of miR-107 and its signaling pathways in diseases. J Recept Signal Transduct Res 34(5): 338-41. (2014).
[13]
Singh R, Masuda ES, Payan DG. Discovery and development of spleen tyrosine kinase (SYK) inhibitors. J Med Chem 55(8): 3614-43. (2012).
[14]
Abdel-Magid AF. Spleen tyrosine kinase inhibitors (syk) as potential treatment for autoimmune and inflammatory disorders: patent highlight. ACS Med Chem Lett 4(1): 18-9. (2013).
[15]
Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-beta production and Tau hyperphosphorylation. J Biol Chem 289(49): 33927-44. (2014).
[16]
Venkatesan N, Deepa PR, Khetan V, Krishnakumar S. Computational and in vitro investigation of mirna-gene regulations in retinoblastoma pathogenesis: miRNA mimics strategy. Bioinform Biol Insights 9: 89-101. (2015).
[17]
Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46(5): 705-16. (1986).
[18]
Abu-Amer Y. NF-kappaB signaling and bone resorption. Osteoporos Int 24(9): 2377-86. (2013).
[19]
Kim E, Son YJ, Yang Y, Shen T, Kim I, Aravinthan A, et al. 1-(2,3-Dibenzimidazol-2-ylpropyl)-2-methoxybenzene Is a Syk Inhibitor with Anti-Inflammatory Properties. Molecules 21(4): 508. (2016).
[20]
Song SY, Jung YY, Hwang CJ, Lee HP, Sok CH, Kim JH, et al. Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-kappaB activation in cultured astrocytes and microglial BV-2 cells. J Neuroinflam 11: 118. (2014).
[21]
Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, et al. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 89(5): 1308-12. (2004).
[22]
Huang M, Liang Y, Chen H, Xu B, Chai C, Xing P. The role of fluoxetine in activating wnt/beta-catenin signaling and repressing beta-amyloid production in an alzheimer mouse model. Front Aging Neurosci 10: 164. (2018).
[23]
Shu B, Zhang X, Du G, Fu Q, Huang L. MicroRNA-107 prevents amyloid-beta-induced neurotoxicity and memory impairment in mice. Int J Mol Med 41(3): 1665-72. (2018).
[24]
Moncini S, Lunghi M, Valmadre A, Grasso M, Del Vescovo V, Riva P, et al. The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with implications for Alzheimer’s disease pathogenesis. Mol Neurobiol 54(6): 4329-42. (2017).
[25]
Wang WX, Wilfred BR, Madathil SK, Tang G, Hu Y, Dimayuga J, et al. miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol 177(1): 334-45. (2010).
[26]
Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, et al. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28(5): 1213-23. (2008).
[27]
Nelson PT, Wang WX. MiR-107 is reduced in Alzheimer’s disease brain neocortex: validation study. J Alzheimers Dis 21(1): 75-9. (2010).
[28]
Hatterer E, Benon A, Chounlamountri N, Watrin C, Angibaud J, Jouanneau E, et al. Syk kinase is phosphorylated in specific areas of the developing nervous system. Neurosci Res 70(2): 172-82. (2011).
[29]
Kohler C, Fuhr V, Dinekov M. Distribution of spleen tyrosine kinase and tau phosphorylated at tyrosine 18 in a mouse model of tauopathy and in the human hippocampus. Brain Res 1677: 1-13. (2017).
[30]
Schweig JE, Yao H, Beaulieu-Abdelahad D, Ait-Ghezala G, Mouzon B, Crawford F, et al. Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase. Acta Neuropathol Commun 5(1): 69. (2017).
[31]
Mohr S, Doebele C, Comoglio F, Berg T, Beck J, Bohnenberger H, et al. Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia Cancer Cell 31(4): 549-62 e11 (2017).
[32]
Maes OC, Schipper HM, Chertkow HM, Wang E. Methodology for discovery of Alzheimer’s disease blood-based biomarkers. J Gerontol A Biol Sci Med Sci 64(6): 636-45. (2009).
[33]
Maes OC, Xu S, Yu B, Chertkow HM, Wang E, Schipper HM. Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiol Aging 28(12): 1795-809. (2007).
[34]
Wang XY, Tang SS, Hu M, Long Y, Li YQ, Liao MX, et al. Leukotriene D4 induces amyloid-beta generation via CysLT(1)R-mediated NF-kappaB pathways in primary neurons. Neurochem Int 62(3): 340-7. (2013).
[35]
Zeng KW, Zhang T, Fu H, Liu GX, Wang XM. Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-kappaB signaling pathway in lipopolysaccharide-induced microglia. Eur J Pharmacol 692(1-3): 29-37. (2012).
[36]
Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 148(6): 1204-22. (2012).
[37]
Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VL, et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16(9): 564-74. (2015).
[38]
Kohr MA, Parrish JM, Neef NA, Driessen JR, Hallinan PC. Communication skills training for parents: experimental and social validation. J Appl Behav Anal 21(1): 21-30. (1988).
[39]
Davis PS, Babaria A, March DE, Goldberg RD. Primary amyloidosis of the ureter and renal pelvis. Urol Radiol 9(3): 158-60. (1987).
[40]
Hunt C, Morimoto RI. Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci USA 82(19): 6455-9. (1985).
[41]
Kong Y, Wu J, Yuan L. MicroRNA expression analysis of adult-onset Drosophila Alzheimer’s disease model. Curr Alzheimer Res 11(9): 882-91. (2014).
[42]
Barbash S, Soreq H. Threshold-independent meta-analysis of Alzheimer’s disease transcriptomes shows progressive changes in hippocampal functions, epigenetics and microRNA regulation. Curr Alzheimer Res 9(4): 425-35. (2012).
[43]
Dencker L. Accumulation of retinoids in embryonic neural and neural crest cells as part of the mechanism of teratogenesis. Ups J Med Sci 91(3): 295-8. (1986).

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy