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Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models.
PLoS One 2018; 13(5):e0196929Plos

Abstract

MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Authors+Show Affiliations

Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. Division of Phenotype Disease Analysis, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29738527

Citation

Higaki, Sayuri, et al. "Defensive Effect of microRNA-200b/c Against Amyloid-beta Peptide-induced Toxicity in Alzheimer's Disease Models." PloS One, vol. 13, no. 5, 2018, pp. e0196929.
Higaki S, Muramatsu M, Matsuda A, et al. Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models. PLoS ONE. 2018;13(5):e0196929.
Higaki, S., Muramatsu, M., Matsuda, A., Matsumoto, K., Satoh, J. I., Michikawa, M., & Niida, S. (2018). Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models. PloS One, 13(5), pp. e0196929. doi:10.1371/journal.pone.0196929.
Higaki S, et al. Defensive Effect of microRNA-200b/c Against Amyloid-beta Peptide-induced Toxicity in Alzheimer's Disease Models. PLoS ONE. 2018;13(5):e0196929. PubMed PMID: 29738527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models. AU - Higaki,Sayuri, AU - Muramatsu,Masashi, AU - Matsuda,Akio, AU - Matsumoto,Kenji, AU - Satoh,Jun-Ichi, AU - Michikawa,Makoto, AU - Niida,Shumpei, Y1 - 2018/05/08/ PY - 2018/01/15/received PY - 2018/04/23/accepted PY - 2018/5/9/entrez PY - 2018/5/9/pubmed PY - 2018/8/2/medline SP - e0196929 EP - e0196929 JF - PloS one JO - PLoS ONE VL - 13 IS - 5 N2 - MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/29738527/Defensive_effect_of_microRNA_200b/c_against_amyloid_beta_peptide_induced_toxicity_in_Alzheimer's_disease_models_ L2 - http://dx.plos.org/10.1371/journal.pone.0196929 DB - PRIME DP - Unbound Medicine ER -