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

Mohammad Ali 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 Wahlestedt

Research output: Contribution to journalArticlepeer-review

888 Scopus citations

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 (US)
Pages (from-to)723-730
Number of pages8
JournalNature medicine
Volume14
Issue number7
DOIs
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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