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

Mohammad A Faghihi, Farzaneh Modarresi, Ahmad M. Khalil, Douglas E. Wood, Barbara G. Sahagan, Todd E. Morgan, Caleb E. Finch, Georges St. Laurent, Paul J. Kenny, Claes R Wahlestedt

Research output: Contribution to journalArticle

788 Citations (Scopus)

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 β-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-β 1-42 (Aβ 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Aβ 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 Aβ 1-42 in Alzheimer's disease.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
JournalNature Medicine
Volume14
Issue number7
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

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Amyloid Precursor Protein Secretases
Untranslated RNA
Alzheimer Disease
Messenger RNA
Long Noncoding RNA
Amyloid beta-Protein Precursor
RNA Stability
Amyloid
Transgenic Mice
Proteins
Drive
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase. / Faghihi, Mohammad A; Modarresi, Farzaneh; Khalil, Ahmad M.; Wood, Douglas E.; Sahagan, Barbara G.; Morgan, Todd E.; Finch, Caleb E.; St. Laurent, Georges; Kenny, Paul J.; Wahlestedt, Claes R.

In: Nature Medicine, Vol. 14, No. 7, 01.07.2008, p. 723-730.

Research output: Contribution to journalArticle

Faghihi, MA, Modarresi, F, Khalil, AM, Wood, DE, Sahagan, BG, Morgan, TE, Finch, CE, St. Laurent, G, Kenny, PJ & Wahlestedt, CR 2008, 'Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase', Nature Medicine, vol. 14, no. 7, pp. 723-730. https://doi.org/10.1038/nm1784
Faghihi, Mohammad A ; Modarresi, Farzaneh ; Khalil, Ahmad M. ; Wood, Douglas E. ; Sahagan, Barbara G. ; Morgan, Todd E. ; Finch, Caleb E. ; St. Laurent, Georges ; Kenny, Paul J. ; Wahlestedt, Claes R. / Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase. In: Nature Medicine. 2008 ; Vol. 14, No. 7. pp. 723-730.
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