AUTHOR=Wang Linlin , Liu Jianghong , Wang Qian , Jiang Hailun , Zeng Li , Li Zhuorong , Liu Rui 

TITLE=MicroRNA-200a-3p Mediates Neuroprotection in Alzheimer-Related Deficits and Attenuates Amyloid-Beta Overproduction and Tau Hyperphosphorylation via Coregulating BACE1 and PRKACB

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00806

DOI=10.3389/fphar.2019.00806

ISSN=1663-9812

ABSTRACT=<p>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, because of 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 <italic>in vitro</italic>, 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 enzyme-linked immunosorbent assay (ELISA) techniques. miR-200a-3p was confirmed to be depressed in microarray miRNA profile analysis <italic>in vitro</italic> and <italic>in vivo</italic>, 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 Aβ<sub>1-42</sub> and tau phosphorylation levels <italic>in vitro</italic>. Further mechanistic studies revealed that miR-200a-3p reduced the production of Aβ<sub>1-42</sub> and decreased hyperphosphorylation of tau by regulating the protein translocation of <italic>BACE1</italic> and the protein kinase cAMP-activated catalytic subunit beta (<italic>PRKACB</italic>) associated with the three prime untranslated regions, 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 increases in Aβ<sub>1-42</sub> and tau hyperphosphorylation levels, involving the epitopes threonine 205 and 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 <italic>via</italic> suppression of the expression of BACE1 and synergistically decreasing the hyperphosphorylation of tau <italic>via</italic> attenuation of the expression of PKA.</p>