MiR-22-3p Regulates Amyloid β Deposit in Mice Model of Alzheimer's Disease by Targeting Mitogen-activated Protein Kinase 14

Author(s): Qiling Ji*, Xuemei Wang, Jianxin Cai, Xiangnan Du, Hui Sun, Nan Zhang

Journal Name: Current Neurovascular Research

Volume 16 , Issue 5 , 2019

Become EABM
Become Reviewer


Propose: To investigate whether miR-22-3p is able to regulate AD development and its molecular mechanism.

Methods: Morris water maze test was performed to test the spatial memory. Quantitative polymerase chain reaction (qPCR) was used to assess the expression level of miR-22-3p. The enzymelinked immunosorbent assay (ELISA) was used to assess the levels of Aβ40 and Aβ42. Immunoblotting analysis was performed to detect the protein expression levels of amyloid precursor protein (APP), mitogen-activated protein kinase 14 (MAPK14) and beta-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1). Luciferase assay was used to identify the interaction between miR- 22-3p and MAPK14. The tetrazolium dye (MTT) colorimetric assay was used to test the influence of miR-22-3p overexpression on cell viability. Flow cytometry analysis was performed to evaluate the effect of miR-22-3p overexpression on cell apoptosis.

Results: Morris water maze test showed that mice model of AD had impaired spatial memory, which was able to be ameliorated by miR-22-3p overexpression. Immunoblotting analysis revealed that the protein expression levels of APP, MAPK14 and BACE1 were enhanced in AD model, which could be prevented by miR-22-3p overexpression. ELISA showed that Aβ40 and Aβ42 levels were dramatically increased in AD model, which were inhibited by miR-22-3p overexpression. Luciferase assay and immunoblotting analysis indicated that miR-22-3p targeted and regulated MAPK14 expression.

Conclusion: MiR-22-3p overexpression reduced Aβ deposit and alleviated AD symptoms by targeting and regulating MAPK14 expression, which ameliorated AD symptoms.

Keywords: Alzheimer's disease, MiR-22-3p, MAPK14, BACE1, microRNA, amyloid precursor protein.

Hodson RJN. Alzheimer’s disease. Nature 2018; 559(7715): S1-.https://www.ncbi.nlm.nih.gov/pubmed/30046078/
[PMID: 30046078]
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.https://www.ncbi.nlm.nih.gov/pubmed/28533191
[PMID: 28533191]
Liu D, Tang H, Li XY, et al. Targeting the HDAC2/HNF-4A/miR-101b/AMPK pathway rescues tauopathy and dendritic abnormalities in Alzheimer’s disease. Mol Ther 2017; 25(3): 752.https://www.ncbi.nlm.nih.gov/pubmed/28202389
[PMID: 28202389]
Xu Y, Ping C, Wang X, Yao J, Zhuang SJNL. miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors. Neurosci Lett 2018; 670: 94-104.https://www.ncbi.nlm.nih.gov/pubmed/29378298
[PMID: 29378298]
Lau P, Bossers K, Salta E, et al. Alteration of the microRNA network during the progression of Alzheimer’s disease. EMBO Mol Med 2013; 5(10): 1613-34.https://www.ncbi.nlm.nih.gov/pubmed/24014289
[PMID: 24014289]
Zhang B, Chen C-F, Wang A-H, Lin Q-F. MiR-16 regulates cell death in Alzheimer’s disease by targeting amyloid precursor protein. Eur Rev Med Pharmacol Sci 2015; 19(21): 4020.https://www.ncbi.nlm.nih.gov/pubmed/26592823
[PMID: 26592823]
Li Q, Li X, Wang L, Zhang Y, Chen L. miR-98-5p acts as a target for Alzheimer’s disease by regulating Aβ production through modulating SNX6 expression. J Mol Neurosci 2016; 60(4): 413-20.https://www.ncbi.nlm.nih.gov/pubmed/27541017
[PMID: 27541017]
Cong L, Kong X, Wang J, et al. Association between SORL1 polymorphisms and the risk of Alzheimer’s disease. J Integr Neurosci 2017; 17(5): 1-13.https://www.ncbi.nlm.nih.gov/pubmed/29036834
[PMID: 29036834]
Zhao W, Li LJP. SP1-induced upregulation of long non-coding RNA HCP5 promotes the development of osteosarcoma. Pathol Res Pract 2019; 215(3): 439.https://www.ncbi.nlm.nih.gov/pubmed/30554864
[PMID: 30554864]
Sochor M, Basova P, Pesta M, et al. Oncogenic MicroRNAs: MiR-155, miR-19a, miR-181b, and miR-24 enable monitoring of early breast cancer in serum. BMC Cancer 2014; 14(1): 448.https://www.ncbi.nlm.nih.gov/pubmed/24938880
[PMID: 24938880]
Gong G, An F, Yu W, Ming B, Yu LJ, Wei CJO. miR-15b represses BACE1 expression in sporadic Alzheimer’s disease. Oncotarget 2017; 8(53): 91551-7.https://www.ncbi.nlm.nih.gov/pubmed/29207665
[PMID: 29207665]
An F, Gong G, Yu W, Ming B, Yu L, Wei CJO. MiR-124 acts as a target for Alzheimer’s disease by regulating BACE1. Oncotarget 2017; 8(69): 114065-71.https://www.ncbi.nlm.nih.gov/pubmed/29371969
[PMID: 29371969]
Kim J, Yoon H, Chung DE, Brown JL, Belmonte KC, Kim J. miR‐186 is decreased in aged brain and suppresses BACE 1 expression. J Neurochem 2016; 137(3): 436-45.https://www.ncbi.nlm.nih.gov/pubmed/26710318
[PMID: 26710318]
Hébert SS, Horré K, Nicolaï L, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/β-secretase expression. Proc Natl Acad Sci USA 2008; 105(17): 6415-20.https://www.ncbi.nlm.nih.gov/pubmed/18434550
[PMID: 18434550]
Lukiw WJ, Zhao Y. Cui JGJJoBC. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 2008; 283(46): 31315.https://www.ncbi.nlm.nih.gov/pubmed/18801740
[PMID: 18801740]
Wang Y, Veremeyko T, Wong AH-K, et al. Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer’s disease. Neurobiol Aging 2017; 51: 156-66.https://www.ncbi.nlm.nih.gov/pubmed/28089352
[PMID: 28089352]
Kim J, Kwon J, Kim M, Do J, Lee D, Han HJPJ. Low-dielectric-constant polyimide aerogel composite films with low water uptake. Polym J 2016; 48(7): 829-34.https://www.nature.com/articles/pj201637
Honghe Z, Jinlong T, Chen L, et al. MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells. Cancer Lett 2015; 356(2): 781-90.https://www.ncbi.nlm.nih.gov/pubmed/25449431
[PMID: 25449431]
Caracciolo D, Martino MTD, Amodio N, et al. miR-22 suppresses DNA ligase III addiction in multiple myeloma. Leukemia 2018; 33(Suppl. 1): 1.https://www.nature.com/articles/s41375-018-0238-2
Wang WX, Huang Q, Hu Y, Stromberg AJ, Nelson PTJAN. 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.https://www.ncbi.nlm.nih.gov/pubmed/20936480
[PMID: 20936480]
Ana J, Roger M, Santos MDF. Silva, Ruth LCJPO. MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington’s disease-related mechanisms. Acta Neuropathol 2013; 8(1)e54222https://www.ncbi.nlm.nih.gov/pubmed/20936480
[PMID: 20936480]
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3(6): 1101-8.https://www.ncbi.nlm.nih.gov/pubmed/18546601
[PMID: 18546601]
Li-Shu G, Hong-Xia L, Chun-Yang L, et al. Vitamin D3 enhances antitumor activity of metformin in human bladder carcinoma SW-780 cells. Pharmazie 2015; 70(2): 123-8.https://www.ncbi.nlm.nih.gov/pubmed/25997253
[PMID: 25997253]
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.https://www.ncbi.nlm.nih.gov/pubmed/22926857
[PMID: 22926857]
Yang Q, Zhao Q, Yin Y. miR-133b is a potential diagnostic biomarker for Alzheimer’s disease and has a neuroprotective role. Exp Ther Med 2019; 18(4): 2711-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755445/
[PMID: 31572518]
Zeng Z, Liu Y, Zheng W, et al. MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer’s disease via downregulating SOX6. Cell Cycle 2019; 18(22): 3095-110.https://www.ncbi.nlm.nih.gov/pubmed/31564203
[PMID: 31564203]
Alam J, Scheper WJA. Targeting neuronal MAP14/p38α activity to modulate autophagy in the Alzheimer disease brain. Autophagy 2016; 12(12): 2516-20.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173254/
[PMID: 27715387]
Feng T, Tammineni P, Agrawal C, Jeong YY, Cai Q. Autophagy-mediated regulation of BACE1 trafficking and degradation. J Biol Chem 2017; 292(5): 1679-90.https://www.ncbi.nlm.nih.gov/pubmed/28028177
[PMID: 28028177]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [473 - 480]
Pages: 8
DOI: 10.2174/1567202616666191111124516
Price: $65

Article Metrics

PDF: 26