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Cited by 1,416Alzheimer's disease research and treatmentsCancer-related molecular mechanisms researchDementia and Cognitive Impairment Research

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

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Faghihi, Mohammad Ali, Modarresi, Farzaneh, Khalil, Ahmad M, Wood, Douglas E, Sahagan, Barbara G, Morgan, Todd E, Finch, Caleb E, St. Laurent III, Georges +2 more·2008·Nature Medicine
DOI 10.1038/nm1784PMC PMC2826895
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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.

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Cited by

Sorted by citations

Authors
Faghihi, M. A., Modarresi, F., Khalil, A. M., Wood, D. E., Sahagan, B. G., Morgan, T. E., Finch, C. E., St. Laurent III, G., Kenny, P. J., & Wahlestedt, C.
Affiliations
  • Scripps Research Institute (US)
  • Pfizer (United States) (US)
  • University of Southern California (US)
Corresponding author
Wahlestedt, Claes
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2008-06-29
Volume
14
Issue
7
Pages
723-730
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm1784
PMC
PMC2826895
OpenAlex
W2130313087
Cited by
1,416
References
6
Citations by year
2026: 25 · 2025: 52 · 2024: 75 · 2023: 54 · 2022: 73 · 2021: 130 · 2020: 106 · 2019: 106 · 2018: 117 · 2017: 94 · 2016: 95 · 2015: 104 · 2014: 103 · 2013: 100 · 2012: 71
FWCI
25.12
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R21AG029290, AG 029290)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, long non-coding RNA, BACE1, beta-secretase, antisense transcripts, amyloid-beta 42, amyloid precursor protein, feedforward control, mRNA stability, post-transcriptional regulation, amyloid precursor protein transgenic mice
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Middle Aged, Models, Genetic, Neuroblastoma, Peptide Fragments, Protein Processing, Post-Translational, RNA, Messenger, Transcription, Genetic, Transfection, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, RNA, Untranslated, Feedback, Physiological, RNA, Small Interfering, Cell Line, Tumor, Mice, Amyloid Precursor Protein Secretases

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