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Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons

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Abstract

One major pathological hallmark of Alzheimer’s disease (AD) is the accumulation of senile plaques mainly composed of neurotoxic amyloid beta-peptide (Aβ) in the patients’ brains. Sonic hedgehog (SHH) is a morphogen critically involved in the embryonic development of the central nervous system (CNS). In the present study, we tested whether Aβ may induce SHH expression and explored its underlying mechanisms. We found that both Aβ25-35 and Aβ1-42 enhanced SHH expression in the primary cortical neurons derived from fetal rat brains. Immunohistochemistry revealed heightened expression of SHH in the cortex and hippocampus of aged (9 and 12 months old) AD transgenic mouse brains as compared to age-matched littermate controls. Chromatin immunoprecipitation (ChIP) assay demonstrated that Aβ25-35 enhanced binding of hypoxia-inducible factor-1 (HIF-1) to the promoter of the Shh gene in primary cortical cultures; consistently, Aβ25-35 induction of SHH was abolished by HIF-1α small interfering RNA (siRNA). Aβ25-35 also time-dependently induced inhibitor of differentiation-1 (Id1) that has been shown to stabilize HIF-1α; further, Aβ25-35-mediated induction of HIF-1α and SHH was both suppressed by Id1 siRNA. Pharmacological induction of HIF-1α by cobalt chloride and application of the cell-permeable recombinant Id1 proteins were both sufficient to induce SHH expression. Finally, both the SHH pathway inhibitor cyclopamine and its neutralizing antibody attenuated Aβ cytotoxicity, albeit to a minor extent. These results thus established a signaling cascade of “Aβ → Id1 → HIF-1 → SHH” in primary rat cortical cultures; furthermore, SHH may in part contribute to Aβ neurotoxicity.

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Acknowledgments

This study was supported by the National Science Council/Ministry of Science and Technology in Taiwan (NSC 101-2314-B-010-042MY2 and MOST 103-2314-B-010-013MY3 to Ding-I Yang; NSC 102-2314-B-038-024 to Liang-Yo Yang), Ministry of Education in Taiwan Aim for the Top University Plan (103AC-B5 to Ding-I Yang), Department of Health in Taipei City Government (10201-62-067 and 10301-62-003 to Ding-I Yang and Chi-Shin Hwang), and Cheng Hsin General Hospital (102F218C12 and 103F003C16 to Ding-I Yang and Jiu-Haw Yin).

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All authors declare no actual or potential conflicts of interest.

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Authors and Affiliations

  1. Institute of Brain Science and Brain Research Center, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 11221, Taiwan

    Yu-Hsing Hung, Shih-Hsin Chang, Chao-Tzu Huang & Ding-I Yang

  2. Department of Neurology, Cheng Hsin General Hospital, Taipei City, 11212, Taiwan

    Jiu-Haw Yin

  3. Department of Neurology, Taipei City Hospital, Taipei City, 10341, Taiwan

    Chi-Shin Hwang

  4. Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan

    Liang-Yo Yang

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  1. Yu-Hsing Hung
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Correspondence to Ding-I Yang.

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Yu-Hsing Hung and Shih-Hsin Chang contributed equally to this work.

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Hung, YH., Chang, SH., Huang, CT. et al. Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons. Mol Neurobiol 53, 793–809 (2016). https://doi.org/10.1007/s12035-014-9046-5

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