Effects of microRNA-298 on APP and BACE1 translation differ according to cell type and 3′-UTR variation

• Published in: Scientific reports Vol. 12; no. 1; pp. 3074 - 16
• Main Authors: Wang, Ruizhi, Lahiri, Debomoy K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; 631/378; 631/45; 692/308; Alzheimer's disease; Amyloid; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Cell Line; Genetic Variation; Humanities and Social Sciences; Humans; Kinases; MicroRNAs; MicroRNAs - genetics; MicroRNAs - physiology; miRNA; multidisciplinary; Neurodegenerative diseases; Neurofibrillary tangles; Non-coding RNA; Peptides; Protein Biosynthesis - genetics; Proteins; Science; Science (multidisciplinary); Senile plaques; Translation; β-Site APP-cleaving enzyme 1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-05164-4

Alzheimer’s disease (AD) is marked by neurofibrillary tangles and senile plaques composed of amyloid β (Aβ) peptides. However, specific contributions of different cell types to Aβ deposition remain unknown. Non-coding microRNAs (miRNA) play important roles in AD by regulating translation of major associated proteins, such as Aβ precursor protein (APP) and β-site APP-cleaving enzyme (BACE1), two key proteins associated with Aβ biogenesis. MiRNAs typically silence protein expression via binding specific sites in mRNAs’ 3′-untranslated regions (3′-UTR). MiRNAs regulate protein levels in a cell-type specific manner; however, mechanisms of the variation of miRNA activity remain unknown. We report that miR-298 treatment reduced native APP and BACE1 protein levels in an astrocytic but not in a neuron-like cell line. From miR-298’s effects on APP-3′-UTR activity and native protein levels, we infer that differences in APP 3′-UTR length could explain differential miR-298 activity. Such varied or truncated, but natural, 3′-UTR specific to a given cell type provides an opportunity to regulate native protein levels by particular miRNA. Thus, miRNA’s effect tailoring to a specific cell type, bypassing another undesired cell type with a truncated 3′-UTR would potentially advance clinically-relevant translational research.