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

Abstract

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.

MicroRNAs Modulate the Pathogenesis of Alzheimer’s Disease: An In Silico Analysis in the Human Brain

“…Moreover, miR-219 mitigated glutamate neurotoxicity in cultured hippocampal neurons, targeting calmodulin-dependent protein kinase II γ [ 51 ]. Another study found that miR-219-5p was downregulated in the brain of AD patients and associated with the increase of TTBK1 and GSK-3β, influencing Tau phosphorylation [ 52 ].…”

MicroRNAs in Alzheimer’s Disease: Function and Potential Applications as Diagnostic Biomarkers

“…Overexpression of miR-125b leads to the upregulation of the p35, CDK5, and p44/42 MAPK (Erk1/2) signaling pathways, while the phosphatases DUSP6 and PPP1CA and the antiapoptotic factor Bcl-W are downregulated as direct targets of miR-125b, which promotes tau hyperphosphorylation (Banzhaf-Strathmann et al, 2014;Ma et al, 2017). GSK3 is also an important kinase for tau protein phosphorylation, and miR-219-5p downregulates GSK3 to inhibit tau phosphorylation in AD (Li et al, 2019).…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…Abnormally phosphorylated tau protein is another key pathological hallmark of AD. Li et al find that microRNA − 219-5p is significantly upregulated in brain tissues of AD patients, contributing to tau phosphorylation and AD progression ( 122 ). MicroRNA-125b promotes the phosphorylation of tau by activating cyclin-dependent kinase 5 (CDK5) and p35/25, and microRNA-125b is increased in AD patients ( 123 ).…”