Article abstract
Nature Medicine 14, 723 - 730 (2008)
Published online: 29 June 2008 | doi:10.1038/nm1784
Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of 
-secretase
Mohammad Ali Faghihi1,2, Farzaneh Modarresi1, Ahmad M Khalil1, Douglas E Wood3, Barbara G Sahagan3, Todd E Morgan4, Caleb E Finch4, Georges St. Laurent III5,6, Paul J Kenny7 & Claes Wahlestedt1
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 
-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- 1–42 (A 1–42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional A 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 1–42 in Alzheimer's disease.
- Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
- Department of Molecular Medicine and Surgery, Karolinska Institute, Solna (L1:00), SE-171 76 Stockholm, Sweden.
- Central Nervous System Discovery, Pfizer Global Research and Development, MS 8220-4138 Eastern Point Road, Groton, Connecticut 06340, USA.
- Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA.
- Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, 2300 Eye Street N.W., Washington, DC 20037, USA.
- Immunovirology—Biogenesis Group, University of Antioquia, 1226 Medellín, Colombia.
- Department of Molecular Therapeutics, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
Correspondence to: Claes Wahlestedt1 e-mail: clawah@scripps.edu
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