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

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 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.

• Authors: Mohammad Ali Faghihi, Farzaneh Modarresi, Ahmad M Khalil, Douglas E Wood, Barbara G Sahagan, Todd E Morgan, Caleb E Finch, Georges St Laurent 3rd, Paul J Kenny, Claes Wahlestedt
• Journal: Nature medicine (Nat Med) Vol. 14 Issue 7 Pg. 723-30 (Jul 2008) ISSN: 1546-170X [Electronic] United States
• PMID: 18587408 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (enzymology, etiology, metabolism, physiopathology)
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Aspartic Acid Endopeptidases (genetics, 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, metabolism)
• Transcription, Genetic
• Transfection