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Expression of a noncoding rna is elevated in alzheimer's disease and drives rapid feed-forward regulation of beta-secretase

Academic Article
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Overview

authors

  • Faghihi, M. A.
  • Modarresi, F.
  • Khalil, A. M.
  • Wood, D. E.
  • Sahagan, B. G.
  • Morgan, T. E.
  • Finch, C. E.
  • Laurent, G. S.
  • Kenny, Paul
  • Wahlestedt, C.

publication date

  • July 2008

journal

  • Nature Medicine  Journal

abstract

  • Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease.

subject areas

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides
  • Animals
  • Aspartic Acid Endopeptidases
  • Cell Line, Tumor
  • Feedback, Physiological
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Models, Genetic
  • Neuroblastoma
  • Peptide Fragments
  • Protein Processing, Post-Translational
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA, Untranslated
  • Transcription, Genetic
  • Transfection
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Identity

PubMed Central ID

  • PMC2826895

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1784

PubMed ID

  • 18587408
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Additional Document Info

start page

  • 723

end page

  • 730

volume

  • 14

issue

  • 7

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