Login Register Cart 0
Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Author(s): Dan Wang, Zhifu Fei, Song Luo and Hai Wang*

Volume 17, Issue 1, 2020

Page: [93 - 101] Pages: 9

DOI: 10.2174/1567202617666200128141938

Price: $65

Abstract

Objective: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified.

Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice.

Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice.

Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Keywords: Alzheimer's disease, miR-335-5p, JNK3, β-Amyloid, cognitive deficits, APP/PS1.

« Previous Next »
[1]
Gao, Y.; Tan, L.; Yu, J-T.; Tan, L. Tau in Alzheimer’s disease: Mechanisms and therapeutic strategies. Curr. Alzheimer Res., 2018, 15(3), 283-300.
[http://dx.doi.org/10.2174/1567205014666170417111859] [PMID: 28413986]
[2]
Huang, Y.; Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell, 2012, 148(6), 1204-1222.
[http://dx.doi.org/10.1016/j.cell.2012.02.040] [PMID: 22424230]
[3]
Crimins, J.L.; Pooler, A.; Polydoro, M.; Luebke, J.I.; Spires-Jones, T.L. The intersection of amyloid β and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer’s disease. Ageing Res. Rev., 2013, 12(3), 757-763.
[http://dx.doi.org/10.1016/j.arr.2013.03.002] [PMID: 23528367]
[4]
Denman, R.; Miller, D.L. Novel cleavage of a hammerhead ribozyme targeted to β-amyloid peptide precursor mRNA. Arch. Biochem. Biophys., 1993, 305(2), 392-400.
[http://dx.doi.org/10.1006/abbi.1993.1437] [PMID: 8373177]
[5]
Gravina, S.A.; Ho, L.; Eckman, C.B. Amyloid β protein (A β) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ 40 or Aβ 42(43). J. Biol. Chem., 1995, 270(13), 7013-7016.
[http://dx.doi.org/10.1074/jbc.270.13.7013] [PMID: 7706234]
[6]
Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2), 281-297.
[7]
Bartel, D.P. MicroRNAs: Target recognition and regulatory functions. Cell, 2009, 136(2), 215-233.
[8]
Ansari, A.; Maffioletti, E.; Milanesi, E. PharmaCog Consortium. miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer’s disease. Neurobiol. Aging, 2019, 82, 102-109.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.005] [PMID: 31437718]
[9]
Q L, L W, G Y, W Z, Z H, J L. miR-125a-5p alleviates dysfunction and inflammation of pentylenetetrazol-induced epilepsy through targeting calmodulin-dependent protein kinase IV (CAMK4). Curr. Neurovasc. Res., 2019, 16(4), 365-372.https://www.ncbi.nlm.nih.gov/pubmed/31490757
[PMID: 31490757]
[10]
M J-H, H G-L, C Q, L Y-M. MiR-34a inhibits spinal cord injury and blocks spinal cord neuron apoptosis by activating phatidylinositol 3-kinase (PI3K)/AKT pathway through targeting CD47. Curr. Neurovasc. Res., 2019, 16(4), 373-381.
[11]
Wu, Y.; Xu, D.; Zhu, X.; Yang, G.; Ren, M.Y.W. MiR-106a associated with diabetic peripheral neuropathy through the regulation of 12/15-LOX-meidiated oxidative/nitrative stress. Curr. Neurovasc. Res., 2017, 14(2), 117-124.
[http://dx.doi.org/10.2174/1567202614666170404115912] [PMID: 28393703]
[12]
Ji, Q.; Wang, X.; Cai, J.; Du, X.; Sun, H.; Zhang, N. MiR-22-3p regulates amyloid β deposit in mice model of Alzheimer’s disease by targeting mitogen-activated protein kinase 14. Curr. Neurovasc. Res., 2019, 16(5), 473-480.
[http://dx.doi.org/10.2174/1567202616666191111124516] [PMID: 31713484]
[13]
Wang, Y.; Yang, T.; Zhang, Z. Long non-coding RNA TUG1 promotes migration and invasion by acting as a ceRNA of miR-335-5p in osteosarcoma cells. Cancer Sci., 2017, 108(5), 859-867.
[http://dx.doi.org/10.1111/cas.13201] [PMID: 28205334]
[14]
Wang, Y.; Zeng, X.; Wang, N. Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma. Mol. Cancer, 2018, 17(1), 89.
[http://dx.doi.org/10.1186/s12943-018-0837-6] [PMID: 29753317]
[15]
Li, H.; Xie, S.; Liu, M. The clinical significance of downregulation of mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p in gastric cancer tumorigenesis. Int. J. Oncol., 2014, 45(1), 197-208.
[http://dx.doi.org/10.3892/ijo.2014.2415] [PMID: 24805774]
[16]
Zhang, L.L.; Zhang, L.F.; Guo, X.H.; Zhang, D.Z.; Yang, F.; Fan, Y.Y. Downregulation of miR-335-5p by long noncoding RNA ZEB1-AS1 in gastric cancer promotes tumor proliferation and invasion. DNA Cell Biol., 2018, 37(1), 46-52.
[http://dx.doi.org/10.1089/dna.2017.3926] [PMID: 29215918]
[17]
Wang, F.; Li, L.; Piontek, K.; Sakaguchi, M.; Selaru, F.M. Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology, 2018, 67(3), 940-954.
[http://dx.doi.org/10.1002/hep.29586] [PMID: 29023935]
[18]
Heyn, H.; Engelmann, M.; Schreek, S. MicroRNA miR-335 is crucial for the BRCA1 regulatory cascade in breast cancer development. Int. J. Cancer, 2011, 129(12), 2797-2806.
[http://dx.doi.org/10.1002/ijc.25962] [PMID: 21618216]
[19]
Cao, J.; Zhang, Y.; Yang, J. NEAT1 regulates pancreatic cancer cell growth, invasion and migration though mircroRNA-335-5p/c-met axis. Am. J. Cancer Res., 2016, 6(10), 2361-2374.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088299/
[PMID: 27822425]
[20]
Zhang, J.; Tu, Q.; Bonewald, L.F. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J. Bone Miner. Res., 2011, 26(8), 1953-1963.
[http://dx.doi.org/10.1002/jbmr.377] [PMID: 21351149]
[21]
Tornero-Esteban, P.; Rodríguez-Rodríguez, L.; Abásolo, L. Signature of microRNA expression during osteogenic differentiation of bone marrow MSCs reveals a putative role of miR-335-5p in osteoarthritis. BMC Musculoskelet. Disord., 2015, 16(1), 182.
[http://dx.doi.org/10.1186/s12891-015-0652-9] [PMID: 26243143]
[22]
Zhang, L.; Tang, Y.; Zhu, X. Overexpression of MiR-335-5p promotes bone formation and regeneration in mice. J. Bone Miner. Res., 2017, 32(12), 2466-2475.
[http://dx.doi.org/10.1002/jbmr.3230] [PMID: 28846804]
[23]
Lin, X.; Wu, L.; Zhang, Z. MiR-335-5p promotes chondrogenesis in mouse mesenchymal stem cells and is regulated through two positive feedback loops. J. Bone Miner. Res., 2014, 29(7), 1575-1585.
[http://dx.doi.org/10.1002/jbmr.2163] [PMID: 24347469]
[24]
Si, W.; Ye, S.; Ren, Z. miR 335 promotes stress granule formation to inhibit apoptosis by targeting ROCK2 in acute ischemic stroke. Int. J. Mol. Med., 2019, 43(3), 1452-1466.
[http://dx.doi.org/10.3892/ijmm.2019.4073] [PMID: 30747210]
[25]
Yuan, M.; Yuan, H.; Zhou, C.; Liu, F.; Lin, C.; Tang, Y. The significance of low plasma miR-335 level in patients with acute cerebral infarction may be associated with the loss of control of CALM1 expression. Int. J. Clin. Exp. Med., 2016, 9(10), 19595-19601.
[26]
Wang, W-X.; Huang, Q.; Hu, Y.; Stromberg, A.J.; Nelson, P.T. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: White matter versus gray matter. Acta Neuropathol., 2011, 121(2), 193-205.
[http://dx.doi.org/10.1007/s00401-010-0756-0] [PMID: 20936480]
[27]
Satoh, J. Molecular network of microRNA targets in Alzheimer’s disease brains. Exp. Neurol., 2012, 235(2), 436-446.
[http://dx.doi.org/10.1016/j.expneurol.2011.09.003] [PMID: 21945006]
[28]
Fu, Y.; Hu, X.; Zheng, C. Intrahippocampal miR-342-3p inhibition reduces β-amyloid plaques and ameliorates learning and memory in Alzheimer’s disease. Metab. Brain Dis., 2019, 34(5), 1355-1363.
[http://dx.doi.org/10.1007/s11011-019-00438-9] [PMID: 31134481]
[29]
Oz, M.; Petroianu, G.; Lorke, D.E. E. α7-nicotinic acetylcholine receptors: New therapeutic avenues in Alzheimer’s disease. In: Nicotinic Acetylcholine Receptor Technologies. New York, NY: Humana Press 2016; pp. 149-69.
[30]
Makhaeva, G.F.; Lushchekina, S.V.; Boltneva, N.P. Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease. Sci. Rep., 2015, 5, 13164.
[http://dx.doi.org/10.1038/srep13164] [PMID: 26281952]
[31]
Park, J.H.; Kim, Y.H.; Ahn, J.H. Atomoxetine protects against NMDA receptor-mediated hippocampal neuronal death following transient global cerebral ischemia. Curr. Neurovasc. Res., 2017, 14(2), 158-168.
[http://dx.doi.org/10.2174/1567202614666170328094042] [PMID: 28356001]
[32]
Xiang, K.; Zhao, X.; Li, Y.; Zheng, L.; Wang, J.; Li, Y.H.K.X. Selective 5-HT7 receptor activation may enhance synaptic plasticity through N-methyl-D-aspartate (NMDA) receptor activity in the visual cortex. Curr. Neurovasc. Res., 2016, 13(4), 321-328.
[http://dx.doi.org/10.2174/1567202613666160823164136] [PMID: 27558200]
[33]
Humpel, C. Platelets: Their potential contribution to the generation of Beta-amyloid Plaques in Alzheimer’s disease. Curr. Neurovasc. Res., 2017, 14(3), 290-298.
[http://dx.doi.org/10.2174/1567202614666170705150535] [PMID: 28677497]
[34]
Karch, C.M.; Goate, A.M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry, 2015, 77(1), 43-51.
[http://dx.doi.org/10.1016/j.biopsych.2014.05.006] [PMID: 24951455]
[35]
Nalivaeva, N.N.; Turner, A.J. The amyloid precursor protein: A biochemical enigma in brain development, function and disease. FEBS Lett., 2013, 587(13), 2046-2054.
[http://dx.doi.org/10.1016/j.febslet.2013.05.010] [PMID: 23684647]
[36]
Cole, S.L.; Vassar, R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem., 2008, 283(44), 29621-29625.
[http://dx.doi.org/10.1074/jbc.R800015200] [PMID: 18650431]
[37]
Chang, Y.J.; Chen, Y.R. The coexistence of an equal amount of Alzheimer’s amyloid-β 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway. FEBS J., 2014, 281(11), 2674-2687.
[http://dx.doi.org/10.1111/febs.12813] [PMID: 24720730]
[38]
Walsh, D.M.; Klyubin, I.; Fadeeva, J.V. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 2002, 416(6880), 535-539.
[http://dx.doi.org/10.1038/416535a] [PMID: 11932745]
[39]
K M. MicroRNAs for the treatment of dementia and Alzheimer’s disease. Curr. Neurovasc. Res., 2019, 16(1), 1-2.
[http://dx.doi.org/10.2174/1567202616666190208094159] [PMID: 30732557]
[40]
Tan, L.; Xing, A.; Zhao, D.L. Strong association of lipid metabolism related MicroRNA binding sites polymorphisms with the risk of late onset Alzheimer’s disease. Curr. Neurovasc. Res., 2017, 14(1), 3-10.
[http://dx.doi.org/10.2174/1567202613666161027101100] [PMID: 27897113]
[41]
Li, J.; Chen, W.; Yi, Y.; Tong, Q. miR-219-5p inhibits tau phosphorylation by targeting TTBK1 and GSK-3β in Alzheimer’s disease. J. Cell. Biochem., 2019, 120(6), 9936-9946.
[http://dx.doi.org/10.1002/jcb.28276] [PMID: 30556160]
[42]
Li, J; Wang, H. miR-15b reduces amyloid-β accumulation in SHSY5Y cell line through targetting NF-κB signaling and BACE1. Biosci Rep 2018; 38(6): BSR20180051.
[http://dx.doi.org/10.1042/BSR20180051] [PMID: 29961672]
[43]
Kuan, C-Y.; Yang, D.D.; Roy, D.R.; Davis, R.J.; Rakic, P.; Flavell, R.A. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 1999, 22(4), 667-676.
[http://dx.doi.org/10.1016/S0896-6273(00)80727-8] [PMID: 10230788]
[44]
Réus, G.Z.; Bernardini Dos Santos, M.A.; Abelaira, H.M. Antioxidant therapy alters brain MAPK-JNK and BDNF signaling path-ways in experimental diabetes mellitus. Curr. Neurovasc. Res., 2016, 13(2), 107-114.
[http://dx.doi.org/10.2174/1567202613666160219115832] [PMID: 26891662]
[45]
Colombo, A.; Bastone, A.; Ploia, C. JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol. Dis., 2009, 33(3), 518-525.
[http://dx.doi.org/10.1016/j.nbd.2008.12.014] [PMID: 19166938]
[46]
Yoon, S.O.; Park, D.J.; Ryu, J.C. JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron, 2012, 75(5), 824-837.
[http://dx.doi.org/10.1016/j.neuron.2012.06.024] [PMID: 22958823]
[47]
Ploia, C.; Antoniou, X.; Sclip, A. JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models. J. Alzheimers Dis., 2011, 26(2), 315-329.
[http://dx.doi.org/10.3233/JAD-2011-110320] [PMID: 21628793]
[48]
Wang, J-Z.; Xia, Y-Y.; Grundke-Iqbal, I.; Iqbal, K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J. Alzheimers Dis., 2013, 33(Suppl. 1), S123-S139.
[http://dx.doi.org/10.3233/JAD-2012-129031] [PMID: 22710920]
[49]
Chami, L.; 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., 2012, 7(1), 52.
[http://dx.doi.org/10.1186/1750-1326-7-52] [PMID: 23039869]

Rights & Permissions Print Cite
Article Metrics
20
2
© 2024 Bentham Science Publishers | Privacy Policy