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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00806

MicroRNA-200a-3p mediates neuroprotection in Alzheimer-related deficits and attenuates amyloid-beta overproduction and tau hyperphosphorylation via co-regulating BACE1 and PRKACB

  • 1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, China
  • 2Xuanwu Hospital, Capital Medical University, China

Alzheimer’s disease (AD) is characterized by two landmark pathologies, the overproduction of amyloid-beta peptides (Aβ), predominated by the β-amyloid protein precursor cleaving enzyme 1 (BACE1), and hyperphosphorylation of the microtubule protein, tau, due to an imbalance in a kinase / phosphatase system that involves the activation of the protein kinase A (PKA). Current evidence indicates that brain microRNAs participate in multiple aspects of AD pathology. Here, the role and underlying molecular mechanisms of microRNA-200a-3p (miR-200a-3p) in mediating neuroprotection against AD-related deficits were investigated. The expression of miR-200a-3p was measured in the hippocampus of APP / PS1 and SAMP8 mice and in an AD cell model in vitro, as well as in blood plasma extracted from AD patients. The targets of miR-200a-3p were determined using bioinformatics and dual-luciferase assay analyses. In addition, cell apoptosis was detected using flow cytometry and related protein levels were measured using Western blot and ELISA techniques. miR-200a-3p was confirmed to be depressed in microarray miRNA profile analysis in vitro and in vivo, suggesting that miR-200a-3p is a potential biomarker of AD. Subsequently, miR-200a-3p was demonstrated to inhibit cell apoptosis accompanied by the inactivation of the Bax / caspase-3 axis and downregulation of Aβ1-42 and tau phosphorylation levels in vitro. Further mechanistic studies revealed that miR-200a-3p reduced the production of Aβ1-42 and decreased hyperphosphorylation of tau by regulating the protein translocation of BACE1 and the protein kinase cAMP-activated catalytic subunit beta (PRKACB) associated with the three prime untranslated regions (3’-UTRs), respectively. Importantly, the function of miR-200a-3p was reversed by overexpression of BACE1 or PRKACB in cultured cells. This resulted in an elevation in cell apoptosis, and an increase in Aβ1-42, and tau hyperphosphorylation levels, involving the epitopes, threonine 205, serine 202, 214, 396, and 356, the favorable phosphorylated sites of PKA. In conclusion, our study suggests that miR-200a-3p is implicated in the pathology of AD, exerting neuroprotective effects against Aβ-induced toxicity by two possible mechanisms: one involving the inhibition of Aβ overproduction via suppressing the expression of BACE1 and; two, synergistically, decreasing the hyperphosphorylation of tau via attenuating the expression of PKA.

Keywords: Alzheimer’s disease, MiR-200a-3p, BACE1, PRKACB, tau protein, Apoptosis

Received: 10 Dec 2018; Accepted: 21 Jun 2019.

Edited by:

Silvana Gaetani, Sapienza University of Rome, Italy

Reviewed by:

Ana Luisa Carvalho, University of Coimbra, Portugal
Yun Ling, Shanghai Public Health Clinical Center, Fudan University, China  

Copyright: © 2019 Wang, Liu, Wang, Jiang, Li and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Rui Liu, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, 100050, Beijing Municipality, China,