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

Nat Med. 2008 Jul;14(7):723-30. doi: 10.1038/nm1784. Epub 2008 Jun 29.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Amyloid beta-Peptides
  • Peptide Fragments
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA, Untranslated
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse