PMID- 25502463
OWN - NLM
STAT- MEDLINE
DCOM- 20161114
LR  - 20200828
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
VI  - 53
IP  - 2
DP  - 2016 Mar
TI  - Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic 
      Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons.
PG  - 793-809
LID - 10.1007/s12035-014-9046-5 [doi]
AB  - One major pathological hallmark of Alzheimer's disease (AD) is the accumulation 
      of senile plaques mainly composed of neurotoxic amyloid beta-peptide (Abeta) 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 Abeta may induce SHH expression and explored its underlying 
      mechanisms. We found that both Abeta25-35 and Abeta1-42 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 
      Abeta25-35 enhanced binding of hypoxia-inducible factor-1 (HIF-1) to the promoter of 
      the Shh gene in primary cortical cultures; consistently, Abeta25-35 induction of SHH 
      was abolished by HIF-1alpha small interfering RNA (siRNA). Abeta25-35 also 
      time-dependently induced inhibitor of differentiation-1 (Id1) that has been shown 
      to stabilize HIF-1alpha; further, Abeta25-35-mediated induction of HIF-1alpha and SHH was 
      both suppressed by Id1 siRNA. Pharmacological induction of HIF-1alpha 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 Abeta cytotoxicity, albeit to a 
      minor extent. These results thus established a signaling cascade of 
      "Abeta --> Id1 --> HIF-1 --> SHH" in primary rat cortical cultures; furthermore, SHH may 
      in part contribute to Abeta neurotoxicity.
FAU - Hung, Yu-Hsing
AU  - Hung YH
AD  - Institute of Brain Science and Brain Research Center, National Yang-Ming 
      University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 
      11221, Taiwan.
FAU - Chang, Shih-Hsin
AU  - Chang SH
AD  - Institute of Brain Science and Brain Research Center, National Yang-Ming 
      University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 
      11221, Taiwan.
FAU - Huang, Chao-Tzu
AU  - Huang CT
AD  - Institute of Brain Science and Brain Research Center, National Yang-Ming 
      University, No. 155, Section 2, Linong Street, Beitou District, Taipei City, 
      11221, Taiwan.
FAU - Yin, Jiu-Haw
AU  - Yin JH
AD  - Department of Neurology, Cheng Hsin General Hospital, Taipei City, 11212, Taiwan.
FAU - Hwang, Chi-Shin
AU  - Hwang CS
AD  - Department of Neurology, Taipei City Hospital, Taipei City, 10341, Taiwan.
FAU - Yang, Liang-Yo
AU  - Yang LY
AD  - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical 
      University, Taipei City, 11031, Taiwan.
FAU - Yang, Ding-I
AU  - Yang DI
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141215
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (ID1 protein, rat)
RN  - 0 (Inhibitor of Differentiation Protein 1)
RN  - 0 (Shh protein, rat)
SB  - IM
MH  - Alzheimer Disease/metabolism/pathology
MH  - Amyloid beta-Peptides/*toxicity
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/*cytology
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Inhibitor of Differentiation Protein 1/*metabolism
MH  - Mice, Transgenic
MH  - Neurons/drug effects/*metabolism
MH  - Rats, Sprague-Dawley
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Abeta
OT  - HIF-1
OT  - Id1
OT  - Morphogen
EDAT- 2014/12/17 06:00
MHDA- 2016/11/15 06:00
CRDT- 2014/12/16 06:00
PHST- 2014/08/14 00:00 [received]
PHST- 2014/12/02 00:00 [accepted]
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2016/11/15 06:00 [medline]
AID - 10.1007/s12035-014-9046-5 [pii]
AID - 10.1007/s12035-014-9046-5 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2016 Mar;53(2):793-809. doi: 10.1007/s12035-014-9046-5. Epub 2014 
      Dec 15.