Overexpression of miR-26a-5p Suppresses Tau Phosphorylation and Aβ Accumulation in the Alzheimer’s Disease Mice by Targeting DYRK1A

Author(s): Yanni Liu, Lin Wang, Fuheng Xie, Xiao Wang, Yuanyuan Hou, Xiaomeng Wang, Juan Liu*

Journal Name: Current Neurovascular Research

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer
Call for Editor


Objective: It is reported that miR-26a-5p could regulate neuronal development, but its underlying mechanisms in Alzheimer’s disease (AD) progression is unclear.

Methods: APP (swe)/PS1 (ΔE9) transgenic mice served as AD mice. Morris water maze test was used to measure the spatial learning and memory ability of mice. The expressions of miR-26a-5p, DYRK1A, phosphorylated-Tau, Aβ40, and Aβ42 were detected. The relationship between miR- 26a-5p and DYRK1A was explored using dual luciferase reporter assay. The effects of miR-26a- 5p on AD mice was determined.

Results: AD mice walked a lot of wrong ways to find the platform area and the latency time to reach the platform was longer. There was low expression of MiR-26a-5p in AD mice. Overexpression of miR-26a-5p inhibited Tau phosphorylation and Aβ accumulation. MiR-26a-5p negatively regulated DYRK1A via targeting its 3’UTR. In vivo, increased miR-26a-5p down-regulated Aβ40, Aβ42, p-APP and p-Tau levels in AD mice through decreasing DYRK1A. Meanwhile, the swimming path and the latency time, to reach the platform, was shorten after enhancing miR-26a-5p expression.

Conclusion: Overexpression of miR-26a-5p could repress Tau phosphorylation and Aβ accumulation via down-regulating DYRK1A level in AD mice.

Keywords: Alzheimer's disease, miR-26a-5p, DYRK1A, Tau phosphorylation, Aβ accumulation, neurodegenerative disease.

Novais F, Starkstein S. Phenomenology of depression in Alzheimer’s Disease. J Alzheimers Dis 2015; 47(4): 845-55.
[http://dx.doi.org/10.3233/JAD-148004] [PMID: 26401763]
Mancino R, Martucci A, Cesareo M, et al. Glaucoma and Alzheimer Disease: One Age-related neurodegenerative disease of the brain. Curr Neuropharmacol 2018; 16(7): 971-7.
[http://dx.doi.org/10.2174/1570159X16666171206144045] [PMID: 29210654]
Humpel C. Platelets: Their potential contribution to the generation of beta-amyloid plaques in Alzheimer’s Disease. Curr Neurovasc Res 2017; 14(3): 290-8.
[http://dx.doi.org/10.2174/1567202614666170705150535] [PMID: 28677497]
Wang J, Kong X, Cong L, et al. Associations between CD33 rs3865444 and ABCA7 rs3764650 polymorphisms and susceptibility to Alzheimer’s disease. J Integr Neurosci 2018; 17(4): 313-21.
Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies. Nat Rev Neurol 2018; 14(1): 22-39.
[http://dx.doi.org/10.1038/nrneurol.2017.162] [PMID: 29242522]
Laurent C, Buée L, Blum D. Tau and neuroinflammation: What impact for Alzheimer’s disease and tauopathies? Biomed J 2018; 41(1): 21-33.
[http://dx.doi.org/10.1016/j.bj.2018.01.003] [PMID: 29673549]
Kabekkodu SP, Shukla V, Varghese VK, D’ Souza J, Chakrabarty S, Satyamoorthy K. Clustered miRNAs and their role in biological functions and diseases. Biol Rev Camb Philos Soc 2018; 93(4): 1955-86.
[http://dx.doi.org/10.1111/brv.12428] [PMID: 29797774]
Fransquet PD, Ryan J. Micro RNA as a potential blood-based epigenetic biomarker for Alzheimer’s disease. Clin Biochem 2018; 58: 5-14.
[http://dx.doi.org/10.1016/j.clinbiochem.2018.05.020] [PMID: 29885309]
Mushtaq G, Greig NH, Anwar F, et al. miRNAs as Circulating Biomarkers for Alzheimer's Disease and Parkinson's Disease. Medicinal chemistry (Shariqah (United Arab Emirates) 2016; 12(3): 217-5.
Ji Y, Wang D, Zhang B, Lu H. MiR-361-3p inhibits β-amyloid accumulation and attenuates cognitive deficits through targeting BACE1 in Alzheimer’s disease. J Integr Neurosci 2019; 18(3): 285-91.
[http://dx.doi.org/10.31083/j.jin.2019.03.1136] [PMID: 31601077]
Yin Y, Sui C, Meng F, et al. The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species- mediated inactivation of the PI3K/Akt pathway 2017; 16(1): 87.
Rizzo M, Berti G, Russo F, et al. Discovering the miR-26a-5p Targetome in Prostate Cancer Cells. J Cancer 2017; 8(14): 2729-39.
[http://dx.doi.org/10.7150/jca.18396] [PMID: 28928862]
Chang L, Li K, Guo T. miR-26a-5p suppresses tumor metastasis by regulating EMT and is associated with prognosis in HCC. Clin Transl Oncol 2017; 19(6): 695-703.
Li B, Sun H. MiR-26a promotes neurite outgrowth by repressing PTEN expression. Mol Med Rep 2013; 8(2): 676-80.
[http://dx.doi.org/10.3892/mmr.2013.1534] [PMID: 23783805]
Tejedor FJ, Hämmerle B. MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J 2011; 278(2): 223-35.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07954.x] [PMID: 21156027]
Wegiel J, Gong CX, Hwang YW. The role of DYRK1A in neurodegenerative diseases. FEBS J 2011; 278(2): 236-45.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07955.x] [PMID: 21156028]
Branca C, Shaw DM, Belfiore R, et al. Dyrk1 inhibition improves Alzheimer’s disease-like pathology. Aging Cell 2017; 16(5): 1146-54.
[http://dx.doi.org/10.1111/acel.12648] [PMID: 28779511]
Lee ST, Chu K, Jung KH, et al. miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Ann Neurol 2012; 72(2): 269-77.
[http://dx.doi.org/10.1002/ana.23588] [PMID: 22926857]
Jian C, Lu M, Zhang Z, et al. miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP. Life Sci 2017; 182: 104-11.
[http://dx.doi.org/10.1016/j.lfs.2017.05.023] [PMID: 28533191]
Visconte C, Canino J, Guidetti GF, et al. Amyloid precursor protein is required for in vitro platelet adhesion to amyloid peptides and potentiation of thrombus formation. Cell Signal 2018; 52: 95-102.
[http://dx.doi.org/10.1016/j.cellsig.2018.08.017] [PMID: 30172024]
Oboudiyat C, Glazer H, Seifan A, Greer C, Isaacson RS. Alzheimer’s disease. Semin Neurol 2013; 33(4): 313-29.
[http://dx.doi.org/10.1055/s-0033-1359319] [PMID: 24234352]
Li K, Wei Q, Liu FF, et al. Synaptic dysfunction in Alzheimer’s Disease: Aβ, Tau, and epigenetic alterations. Mol Neurobiol 2018; 55(4): 3021-32.
[http://dx.doi.org/10.1007/s12035-017-0533-3] [PMID: 28456942]
Chen J, Zhang K, Xu Y, et al. The role of microRNA-26a in human cancer progression and clinical application. Tumour Biol 2016; 37(6): 7095-108.
[http://dx.doi.org/10.1007/s13277-016-5017-y] [PMID: 27039398]
Guo K, Zheng S, Xu Y, Xu A, Chen B, Wen Y. Loss of miR-26a-5p promotes proliferation, migration, and invasion in prostate cancer through negatively regulating SERBP1. Tumour Biol 2016; 37(9): 12843-54.
[http://dx.doi.org/10.1007/s13277-016-5158-z] [PMID: 27449037]
Huang ZM, Ge HF, Yang CC, et al. MicroRNA-26a-5p inhibits breast cancer cell growth by suppressing RNF6 expression. Kaohsiung J Med Sci 2019; 35(8): 467-73.
[http://dx.doi.org/10.1002/kjm2.12085] [PMID: 31063232]
Song Q, Liu B, Li X, et al. MiR-26a-5p potentiates metastasis of human lung cancer cells by regulating ITGβ8- JAK2/STAT3 axis. Biochem Biophys Res Commun 2018; 501(2): 494-500.
[http://dx.doi.org/10.1016/j.bbrc.2018.05.020] [PMID: 29746867]
Cui C, Xu G, Qiu J, Fan X. Up-regulation of miR-26a promotes neurite outgrowth and ameliorates apoptosis by inhibiting PTEN in bupivacaine injured mouse dorsal root ganglia. Cell Biol Int 2015; 39(8): 933-42.
[http://dx.doi.org/10.1002/cbin.10461] [PMID: 25808510]
Potenza N, Mosca N, Mondola P, Damiano S, Russo A, De Felice B. Human miR-26a-5p regulates the glutamate transporter SLC1A1 (EAAT3) expression. Relevance in multiple sclerosis. Biochim Biophys Acta Mol Basis Dis 2018; 1864(1): 317-23.
[http://dx.doi.org/10.1016/j.bbadis.2017.09.024] [PMID: 28962897]
Li S, Xu C, Fu Y, et al. DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers. Nucleic Acids Res 2018; 46(21): 11202-13.
[http://dx.doi.org/10.1093/nar/gky754] [PMID: 30137413]
Bellmaine SF, Ovchinnikov DA, Manallack DT, et al. Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells. eLife 2017; 6: 6.
[http://dx.doi.org/10.7554/eLife.24502] [PMID: 28884684]
Janel N, Alexopoulos P, Badel A, et al. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer’s disease. Transl Psychiatry 2017; 7(6)e1154
[http://dx.doi.org/10.1038/tp.2017.123] [PMID: 28632203]
Janel N, Sarazin M, Corlier F, et al. Plasma DYRK1A as a novel risk factor for Alzheimer’s disease. Transl Psychiatry 2014.; 4e425
[http://dx.doi.org/10.1038/tp.2014.61] [PMID: 25116835]
Stotani S, Giordanetto F, Medda F. DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem 2016; 8(6): 681-96.
[http://dx.doi.org/10.4155/fmc-2016-0013] [PMID: 27073990]
Kimura R, Kamino K, Yamamoto M, et al. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet 2007; 16(1): 15-23.
[http://dx.doi.org/10.1093/hmg/ddl437] [PMID: 17135279]
Liu F, Liang Z, Wegiel J, et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J 2008; 22(9): 3224-33.
[http://dx.doi.org/10.1096/fj.07-104539] [PMID: 18509201]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 28 September, 2020
Page: [241 - 248]
Pages: 8
DOI: 10.2174/1567202617666200414142637
Price: $65

Article Metrics

PDF: 25