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

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 amy...

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Bibliographic Details
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
Online Access:Get full text
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Summary: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.
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ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/nm1784