Effects of microRNA-298 on APP and BACE1 translation differ according to cell type and 3\u2032-UTR variation

Ruizhi Wang,Debomoy K Lahiri

doi:10.1038/s41598-022-05164-4

Ruizhi Wang, Debomoy K Lahiri

Open Access

https://doi.org/10.1038/s41598-022-05164-4

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Abstract

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.

Highlights

Alzheimer’s disease (AD) is the leading cause of dementia globally and has no effective disease modifying therapy[1]
Many clinical trials based upon the amyloid β (Aβ) plaque cascade hypothesiss, trying to stop or reverse disease progression via altering Aβ levels resulted in unsatisfactory results[7]
The central nervous system (CNS) is a remarkably complex organ system, requiring an complex network of molecular pathways controlling the multitude of diverse cellular activities

Summary

Introduction

Alzheimer’s disease (AD) is the leading cause of dementia globally and has no effective disease modifying therapy[1]. Dysregulation of APP and BACE1 proteins during disease progression has long been the focus of AD research[4,5,6]. Several BACE1 inhibitor clinical trials used small pharmacological molecules including verubecestat, lanabecestat, and LY2886721 and found significant adverse effects in multiple organs besides brain[11,12,13,14,15]. Non-organ-specific overall BACE1 inhibition might account in part for the various adverse e ffects[11]. Regulation of APP and BACE1 in an organ or cell type specific manner is very important, a goal that can be achieved by microRNA (miRNA) regulation of mRNA translation. MiRNAs are short non-coding RNAs with mature length around 22 nucleotides (nt). They function as important regulators of mRNA translation. Seed sequence base pairing with target mRNA 3′-UTR is exactly complementary though base pairing on other sites may not be perfect[17,18]

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