MicroRNA-149 is downregulated in Alzheimer's disease and inhibits β-amyloid accumulation and ameliorates neuronal viability through targeting BACE1.

Wenyan Du,Chengbin Lei,Yong Dong

doi:10.1590/1678-4685-gmb-2020-0064

Abstract

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a critical role in Alzheimer's disease (AD) pathogenesis. This study aimed to investigate the relationship between microRNA-149 (miR-149) and BACE1, and evaluate the clinical significance and biological function of miR-149 in AD progression. Bioinformatics analysis and a luciferase reporter assay were used to confirm the interaction between miR-149 and BACE1. Expression of miR-149 and BACE1 was estimated using quantitative real-time PCR. The clinical significance of miR-149 in AD diagnosis and severity determination was evaluated using ROC analysis. The effect of miR-149 on Aβ accumulation and neuronal viability was analyzed in Aβ-treated SH-SY5Y cells. miR-149 was found directly binding the 3'-UTR of BACE1 and was negatively correlated with BACE1 in AD patients and cell model. Serum miR-149 expression was downregulated in AD patients and served as a potential diagnostic biomarker. The overexpression of miR-149 in Aβ-treated SH-SY5Y cells resulted in inhibited Aβ accumulation and enhanced neuronal viability. This study demonstrated that serum miR-149 is decreased in AD patients and serves as a candidate diagnostic biomarker, and that the overexpression of miR-149 may suppress Aβ accumulation and promote neuronal viability by targeting BACE1 in AD model cells.

Highlights

Neurodegenerative diseases, encompassing Alzheimer disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Huntington disease (HD) and frontotemporal dementia (FTD), make up a series of pathologies characterized by different etiologies with distinct features in morphology and pathophysiology (Sheikh et al, 2013)
Aβ accumulation represents a central event in AD progression, which is produced by the cleavage of amyloid precursor protein (APP) by β-secretases, such as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) (Panza et al, 2019)
The expression of miR-149 and BACE1 in cerebrospinal fluid (CF) samples from 16 AD patients was evaluated, and a negative correlation between CF miR-149 and BACE1 was found in AD patients (r = -0.780, P < 0.001, Figure 1F)

Summary

Introduction

Neurodegenerative diseases, encompassing Alzheimer disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Huntington disease (HD) and frontotemporal dementia (FTD), make up a series of pathologies characterized by different etiologies with distinct features in morphology and pathophysiology (Sheikh et al, 2013). AD is one the most frequent neurodegenerative diseases and represents a leading threat to human health in aging population (Atkinson 2017). Numerous studies focus on AD therapeutic strategies regarding to the regulation of these important pathological events (Chen 2018). The therapeutic strategies for AD had no abilities to prevent or delay disease development, leading to the urgent need to further understand AD pathogenesis, which may provide novel molecular therapeutic targets (Gao et al, 2016). Aβ accumulation represents a central event in AD progression, which is produced by the cleavage of amyloid precursor protein (APP) by β-secretases, such as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) (Panza et al, 2019). Researchers have focused on the inhibitors of BACE1 to improve the treatment of AD (Panza et al, 2019)

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