MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

Cong Cheng,Weiguang Li,Zheng Zhang,Shohei Yoshimura,Qinyu Hao,Chi Zhang,Zhao Wang

doi:10.1074/jbc.m112.381392

Abstract

MicroRNA (miR) dysregulation is found in Alzheimer disease (AD). A disintegrin and metalloprotease 10 (ADAM10) prevents generation of amyloid β (Aβ) and decrease AD pathology. miR-144 suppresses ADAM10 expression and is up-regulated by activator protein-1. miR-144 is a negative regulator of ADAM10 and may be involved in AD pathogenesis. The first work to demonstrate the function of miRNA-144 and its regulation in the pathogenesis of AD. Amyloid β-peptide (Aβ) accumulating in the brain of Alzheimer disease (AD) patients is believed to be the main pathophysiologcal cause of the disease. Proteolytic processing of the amyloid precursor protein by α-secretase ADAM10 (a disintegrin and metalloprotease 10) protects the brain from the production of the Aβ. Meanwhile, dysregulation or aberrant expression of microRNAs (miRNAs) has been widely documented in AD patients. In this study, we demonstrated that overexpression of miR-144, which was previously reported to be increased in elderly primate brains and AD patients, significantly decreased activity of the luciferase reporter containing the ADAM10 3'-untranslated region (3'-UTR) and suppressed the ADAM10 protein level, whereas the miR-144 inhibitor led to an increase of the luciferase activity. The negative regulation caused by miR-144 was strictly dependent on the binding of the miRNA to its recognition element in the ADAM10 3'-UTR. Moreover, we also showed that activator protein-1 regulates the transcription of miR-144 and the up-regulation of miR-144 at least partially induces the suppression of the ADAM10 protein in the presence of Aβ. In addition, we found that miR-451, a miRNA processed from a single gene locus with miR-144, is also involved in the regulation of ADAM10 expression. Taken together, our data therefore demonstrate miR-144/451 is a negative regulator of the ADAM10 protein and suggest a mechanistic role for miR-144/451 in AD pathogenesis.

Highlights

MicroRNA dysregulation is found in Alzheimer disease (AD)
We demonstrated that overexpression of miR-144, which was previously reported to be increased in elderly primate brains and AD patients, significantly decreased activity of the luciferase reporter containing the A disintegrin and metalloprotease 10 (ADAM10) 3؅-untranslated region (3؅-UTR) and suppressed the ADAM10 protein level, whereas the miR-144 inhibitor led to an increase of the luciferase activity
We used a combination of bioinformatics and experimental techniques to demonstrate that miR-144 is a negative regulator of ADAM10, and activator protein-1 (AP1), which can be activated by A␤ and is implicated in AD pathogenesis, is involved in the regulation of miR-144 expression

Summary

Background

MicroRNA (miR) dysregulation is found in Alzheimer disease (AD). A disintegrin and metalloprotease 10 (ADAM10) prevents generation of amyloid ␤ (A␤) and decrease AD pathology. A previous study demonstrates that neuronal overexpression of ADAM10 in APP transgenic mice significantly decreases A␤ generation, amyloid plaque load, and AD pathology, whereas overexpression of a dominant-negative ADAM10 variant enhances A␤ formation [3]. These reports shed light on the important role of ADAM10 in A␤ production and the pathogenesis of AD. We used a combination of bioinformatics and experimental techniques to demonstrate that miR-144 is a negative regulator of ADAM10, and activator protein-1 (AP1), which can be activated by A␤ and is implicated in AD pathogenesis, is involved in the regulation of miR-144 expression. This study presents a mechanism for the ADAM10 protein repression observed in AD patients and provides potential therapeutic targets for the prevention and/or treatment of the disease

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION