Decoy mRNAs reduce β-amyloid precursor protein mRNA in neuronal cells

• Published in: Neurobiology of aging 2006-06, Vol.27 (6), p.787-796
• Main Authors: Westmark, Pamela R., Shin, Hyun C., Westmark, Cara J., Soltaninassab, Syrus R., Reinke, Emily K., Malter, James S.
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - physiology; 3′-UTR regulatory elements; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Base Sequence; Blotting, Northern - methods; Cell Line; Electrophoretic Mobility Shift Assay - methods; Gene Expression Regulation - physiology; Green Fluorescent Proteins - biosynthesis; Humans; Models, Molecular; mRNA stability; Mutagenesis - physiology; Neurons - physiology; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - metabolism; Time Factors; Transcription, Genetic; Transfection - methods; β-Amyloid precursor protein
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2006.03.003

Overproduction of amyloid precursor protein (APP) and β-amyloid likely contribute to neurodegeneration in Alzheimer's disease (AD). In an effort to understand neuronal APP gene regulation, we identified a 52 base element (52sce) immediately downstream from the stop codon that stabilizes APP mRNA. Deletion of this domain drastically destabilized APP mRNAs and reduced APP synthesis in vitro. Chimeric globin-APP mRNAs containing the globin coding sequence fused to the entire APP 3′-UTR, showed regulation similar to full-length APP mRNA. A variety of cytoplasmic lysates contain 52sce RNA binding activity, suggesting cis– trans interactions regulate the element's functionality. Finally, the overexpression of chimeric mRNAs, containing the GFP coding sequence and APP 3′-UTR, dramatically reduced endogenous APP steady-state levels in SH-SY5Y neuroblastoma cells and suggests a novel approach to reduce the amyloid burden in AD patients.