Brain Dicer1 Is Down-Regulated in a Mouse Model of Alzheimer's Disease Via Aβ42-Induced Repression of Nuclear Factor Erythroid 2-Related Factor 2.

Yan Wang,Meiling Lian,Shengzhou Wu,Jing Zhou

doi:10.1007/s12035-020-02036-8

Yan Wang, Meiling Lian + Show 2 more

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https://doi.org/10.1007/s12035-020-02036-8

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Abstract

Dicer1 is a microRNA-processing enzyme which plays critical roles in neuronal survival and neuritogenesis. Dicer1 deletion induces neurodegeneration or degeneration in retinal pigment epithelium, which is associated with oxidative stress. Oxidative stress is thought to be central in the pathogenesis of Alzheimer's disease (AD). Therefore, we hypothesize that Dicer1 may play roles in AD. Using immunoblotting and quantitative real-time PCR, Dicer1 protein and mRNA were reduced in the hippocampi of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-mediated Dicer1 knockdown induced oxidative stress and apoptosis and reduced mitochondrial membrane potential in cultured neurons. Chronic Aβ42 exposure decreased Dicer1 and nuclear factor erythroid 2-related factor 2 (Nrf2) which were reversed by N-acetyl-cystein. Nrf2 overexpression increased Dicer1 mRNA and protein and reverted the Aβ42-induced Dicer1 reduction. We further cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Notably, injection of Dicer1-expressing adenovirus into the hippocampus of the mice significantly improved spatial learning. Altogether, we found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. These results suggest that Dicer1 is a target in AD therapy, especially at the early stage of this disorder. In this study, we found that Dicer1 was reduced in the brain of AD mice which is the first report to examine Dicer1 in AD. We further found (i) that Aβ42 exposure decreased Dicer1 via attenuating Nrf2-ARE signaling and (ii) injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. Altogether, we found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. This study may open new avenues for investigating potential pathognomonics and pathogenesis in AD.

Highlights

Oxidative stress critically underlies the neurodegenerative pathogenesis of Alzheimer's disease (AD)
Using immunoblotting and quantitative real-time PCR, we found that Dicer1 protein and mRNA levels were reduced in the hippocampi of animals of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls
Injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. These findings indicate that Dicer1 expression is reduced in the AD brain and that chronic Aβ exposure decreases Dicer1 levels in neurons via nuclear factor erythroid 2related factor 2 (Nrf2)–antioxidant response elements (ARE) signaling

Summary

Introduction

Oxidative stress critically underlies the neurodegenerative pathogenesis of Alzheimer's disease (AD). The pathogenesis of AD involves the key component of oxidative stress which is dependent on the balance between reactive species and anti-oxidation systems [3]. Amyloid peptide inactivates membrane channel and transporter including sodium/calcium exchanger, calcium ATPase, glutamate and glucose transporter--these hazardous effects involve the roles of reactive oxygen species and lipid peroxidation[79]. Anti-oxidation systems are used to cope with oxidative injury, in which the regulation of the key enzymes or proteins, used for synthesizing glutathione or recycling peroxiredoxins, revolve around a transcriptional factor, nuclear factor erythroid 2related factor 2 (Nrf2) [10, 11]. Nrf is a basic leucine zipper protein that regulates expression of a multitude of antioxidant proteins in response to oxidative injuries. Nrf is retained in cytoplasm by Keap, but upon oxidative stimulation, it is released from the binding and translocated into nucleus, triggering the transcription of antioxidant genes [12]

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