Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-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 US 01.07.2008; Nature Publishing Group
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Antisense RNA; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Development and progression; Feedback, Physiological; Gene expression; Gene Expression Regulation; Genetic aspects; Health aspects; Humans; Infectious Diseases; Male; Metabolic Diseases; Mice; Mice, Transgenic; Middle Aged; Models, Genetic; Molecular Medicine; Neuroblastoma - pathology; Neurosciences; Peptide Fragments - metabolism; Physiological aspects; Protein Processing, Post-Translational; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; RNA, Untranslated - analysis; RNA, Untranslated - metabolism; Transcription, Genetic; Transfection; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm1784

BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression. 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.