miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model

Authors

  • Soon-Tae Lee MD, PhD,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
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  • Kon Chu MD, PhD,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
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  • Keun-Hwa Jung MD, PhD,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
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  • Jin Hee Kim MS,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
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  • Ji-Young Huh MS,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
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  • Hyejin Yoon MS,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
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  • Dong-Kyu Park BS,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
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  • Ji-Yeon Lim BS,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
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  • Jeong-Min Kim MD,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
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  • Daejong Jeon PhD,

    1. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
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  • Hoon Ryu PhD,

    1. Veterans Administration Boston Healthcare System, Boston, MA
    2. Department of Neurology and Pathology, Boston University School of Medicine, Boston, MA
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  • Sang Kun Lee MD, PhD,

    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
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  • Manho Kim MD, PhD,

    Corresponding author
    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
    • Department of Neurology, Seoul National University Hospital, 101, Daehangno, Jongno-gu, Seoul, 110-744, South Korea
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  • Jae-Kyu Roh MD, PhD

    Corresponding author
    1. Department of Neurology, Biomedical Research Institute, Seoul National University HospitalSeoul, South Korea
    2. Program in Neuroscience, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul National University, Seoul, South Korea
    • Department of Neurology, Seoul National University Hospital, 101, Daehangno, Jongno-gu, Seoul, 110-744, South Korea
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Abstract

Objective:

Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice.

Methods:

Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally.

Results:

The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice.

Interpretation:

Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206. ANN NEUROL 2012;72:269–277.

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