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

• Published in: Nature medicine Vol. 14; no. 7; pp. 723 - 730
• Main Authors: Faghihi, Mohammad Ali, Modarresi, Farzaneh, Khalil, Ahmad M, Wood, Douglas E, Sahagan, Barbara G, Morgan, Todd E, Finch, Caleb E, St Laurent Iii, Georges, Kenny, Paul J, Wahlestedt, Claes
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.07.2008
• Subjects: Alzheimer's disease; Enzymes; Medical research; Proteins; Ribonucleic acid; RNA
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1784

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 (A[beta] 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional A[beta] 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 A[beta] 1-42 in Alzheimer's disease. [PUBLICATION ABSTRACT]