title: Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons.
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.
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 11221, Taiwan.
authors.forename: Yu-Hsing
authors.initials: YH
authors.lastname: Hung
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 11221, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 11221, Taiwan.
authors.forename: Chao-Tzu
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Department of Neurology, Cheng Hsin General Hospital, Taipei City, 11212, Taiwan.
authors.forename: Jiu-Haw
authors.initials: JH
authors.lastname: Yin
authors.affiliation: Department of Neurology, Taipei City Hospital, Taipei City, 10341, Taiwan.
authors.forename: Chi-Shin
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan.
authors.forename: Liang-Yo
authors.initials: LY
authors.lastname: Yang
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 11221, Taiwan. diyang@ym.edu.tw.
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D053823:Hedgehog Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497454:ID1 protein, rat; D051798:Inhibitor of Differentiation Protein 1; C546888:Shh protein, rat
keywords: Alzheimer’s disease; Aβ; HIF-1; Id1; Morphogen