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.