Regulatory Role of lncRNA MEG3 Silencing on PI3K/GSK3β/Tau Pathway in a High-Glucose-Induced Cell Model

This study investigated the regulatory role of the long non-coding RNA maternally expressed gene 3 (<i>MEG3</i>) in tau hyperphosphorylation and insulin signaling (<i>PI3K/AKT1/GSK3β</i>) under high-glucose (HG)-induced neurotoxic conditions mimicking Alzheimer's disease pathology. To explore the function of <i>MEG3</i> within a hyperglycemic (Hyp) model, <i>MEG3</i> was silenced using small interfering RNA (siRNA) assay, followed by Western blot analysis, qRT-PCR, and network analyses. The si<i>MEG3</i> + Hyp group had lower levels of <i>AKT1</i> (0.48-fold) and <i>PI3K</i> (0.52-fold) than did the Hyp group. In the si<i>MEG3</i> + Hyp group, <i>GSK3β</i> (2.51-fold) and <i>TNFα</i> (2.38-fold) expressions were higher than were those in the Hyp group, while in the si<i>MEG3</i> group, GSK3β (4.59-fold), microtubule-associated protein <i>TAU</i> (<i>MAPT</i>, <i>TAU</i>) (6.37-fold), interleukin <i>(IL)1β</i> (5.67-fold), <i>IL6</i> (3.29-fold), and tumor necrosis factor-α (<i>TNFα</i>) (3.06-fold) were all significantly upregulated in comparison to the control group. A higher level of p-tau protein was seen in the si<i>MEG3</i> group in comparison to the control group, as well as in the si<i>MEG3</i> + Hyp group in comparison to the Hyp group. Gene ontology analysis following <i>MEG3</i> administration showed that genes downstream of the <i>PI3K</i> pathway were suppressed, whereas genes regulating the neuroinflammatory response were upregulated. The results suggest that the lncRNA <i>MEG3</i> may be a promising therapeutic target in HG-induced neurodegenerative AD.