Long non-coding RNA 00507/miRNA-181c-5p/TTBK1/MAPT axis regulates tau hyperphosphorylation in Alzheimer's disease.

Tau hyperphosphorylation is involved in the progression of Alzheimer's disease (AD). In the present study, we aimed to evaluate the role of linc00507 with respect to modulating Tau phosphorylation in ab AD animal and an Aβ42-SH-SY5Y cell model. Aβ precursor protein (APP)/PS transgenic mice and Aβ42-SH-SY5Y cell model were used to investigate the role of linc00507 in AD. A quantitative real-time polymerase chain reaction evaluated the RNA expression of linc00507, miR-181c-5p and microtubule-associated protein tau (MAPT)/tau-tubulin kinase-1 (TTBK1). The interactions between the genes were investigated through changes in one gene expression by regulating another gene in cells and, in addition, correlation assays were performed in mice. Western blot assays examined the protein expression of MAPT/TTBK1, phosphorylation of tau and signaling proteins P25/P35/GSK3β in response to the regulation of linc00507, miR-181c-5p and MAPT/TTBK1 in cells and also in mice. linc00507 was significantly elevated in hippocampus, and cerebral cortex of APP/PS transgenic mice and AD-like SH-SY5Y cells. It could bind miR-181c-5p and thereby regulate the expression of microtubule-associated protein Tau (MAPT) and tau-tubulin kinase-1 (TTBK1) as a competitive endogenous RNA (ceRNA). MAPT (encoding the tau protein) and TTBK1 (encoding a tau kinase) were identified as direct target genes of miR-181c-5p. Furthermore, linc00507 mediated tau protein hyperphosphorylation by the activation of the P25/P35/GSK3β signaling pathway through regulating MAPT/TTBK1 by sponging miR-181c-5p. The findings of the present highlight the regulatory role of linc00507 in tau phosphorylation miR-181c-5p as ceRNA of MAPT/TTBK1 in vitro and in vivo, providing a basis for novel diagnostic and treatment strategies for AD.

Yan Y ，Yan H ，Teng Y ，Wang Q ，Yang P ，Zhang L ，Cheng H ，Fu S ... -  《-》

miR-219-5p inhibits tau phosphorylation by targeting TTBK1 and GSK-3β in Alzheimer's disease.

As the most common neurodegenerative disease, Alzheimer's disease (AD) is characterized by memory, perception, and behavioral damage, which may ultimately lead to emotional fluctuation and even lethal delirium. Increasing studies indicate that microRNAs (miRNAs) are associated with pathological features of AD. However, the role of miR-219-5p in AD progression is still unclear. In this study, the functions of miR-219-5p were analyzed in vitro and in vivo. miR-219-5p was notably overexpressed in brain tissues of patients with AD. The overexpression of miR-219-5p activated the phosphorylation of Tau-Ser198, Tau-Ser199, Tau-Ser201, and Tau-Ser422. We further showed that miR-219-5p could mediate a decrease in the protein levels of tau-tubulin kinase 1 (TTBK1) and glycogen synthase kinase 3β (GSK-3β) by directly binding to their 3'-untranslated region, thereby promoting the phosphorylation of tau in SH-SY5Y Cells. Rescue experiments further revealed that the phosphorylation of tau-mediated by miR-219-5p was dependent on the inhibition of TTBK1 and GSK-3β. Moreover, suppressing the expression of both TTBK1 and GSK-3β using miR-219-5p remarkably rescued AD-like symptoms in amyloid precursor protein/presenilin 1 mice. Our findings indicate that the upregulation of TTBK1 and GSK-3β mediated by the loss of miR-219-5p is a possible mechanism that contributes to tau phosphorylation and AD progression.

Li J ，Chen W ，Yi Y ，Tong Q ... -  《-》

Micro-RNA-137 Inhibits Tau Hyperphosphorylation in Alzheimer's Disease and Targets the CACNA1C Gene in Transgenic Mice and Human Neuroblastoma SH-SY5Y Cells.

Jiang Y ，Xu B ，Chen J ，Sui Y ，Ren L ，Li J ，Zhang H ，Guo L ，Sun X ... -  《MEDICAL SCIENCE MONITOR》

Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models.

Ikezu S ，Ingraham Dixie KL ，Koro L ，Watanabe T ，Kaibuchi K ，Ikezu T ... -  《Acta Neuropathologica Communications》

Overexpression of miR-26a-5p Suppresses Tau Phosphorylation and Aβ Accumulation in the Alzheimer's Disease Mice by Targeting DYRK1A.

It is reported that miR-26a-5p could regulate neuronal development, but its underlying mechanisms in Alzheimer's disease (AD) progression is unclear. APP (swe)/PS1 (ΔE9) transgenic mice served as AD mice. Morris water maze test was used to measure the spatial learning and memory ability of mice. The expressions of miR-26a-5p, DYRK1A, phosphorylated-Tau, Aβ40, and Aβ42 were detected. The relationship between miR- 26a-5p and DYRK1A was explored using dual luciferase reporter assay. The effects of miR-26a- 5p on AD mice was determined. AD mice walked a lot of wrong ways to find the platform area and the latency time to reach the platform was longer. There was low expression of MiR-26a-5p in AD mice. Overexpression of miR-26a-5p inhibited Tau phosphorylation and Aβ accumulation. MiR-26a-5p negatively regulated DYRK1A via targeting its 3'UTR. In vivo, increased miR-26a-5p down-regulated Aβ40, Aβ42, p-APP and p-Tau levels in AD mice through decreasing DYRK1A. Meanwhile, the swimming path and the latency time, to reach the platform, was shorten after enhancing miR-26a-5p expression. Overexpression of miR-26a-5p could repress Tau phosphorylation and Aβ accumulation via down-regulating DYRK1A level in AD mice.

Liu Y ，Wang L ，Xie F ，Wang X ，Hou Y ，Wang X ，Liu J ... -  《-》