Alternative polyadenylation and miR‐34 family members regulate tau expression

Abstract

Tau pathologically aggregates in Alzheimer’s disease, and evidence suggests that reducing tau expression may be safe and beneficial for the prevention or treatment of this disease. We sought to examine the role of the 3’-untranslated region (3’-UTR) of human tau mRNA in regulating tau expression. Tau expresses two 3’-UTR isoforms, long and short, as a result of alternative polyadenylation. Using luciferase reporter constructs, we found that expression from these isoforms is differentially controlled in human neuroblastoma cell lines M17D and SH-SY5Y. Several microRNAs were computationally identified as candidates that might bind the long, but not short, tau 3’-UTR isoform. A hit from a screen of candidates, miR-34a, was subsequently shown to repress the expression of endogenous tau protein in M17D cells. Conversely, inhibition of endogenously expressed miR-34 family members leads to increased endogenous tau expression. Additionally, through an unbiased screen of fragments of the human tau 3’-UTR using a luciferase reporter assay, we identified several other regions in the long tau 3’-UTR isoform that contain regulatory cis-elements. Improved understanding of the regulation of tau expression by its 3’-UTR may ultimately lead to the development of novel therapeutic strategies for the treatment of Alzheimer’s disease and other tauopathies.

Are microRNAs the Molecular Link Between Metabolic Syndrome and Alzheimer’s Disease?

“…Thus, the loss or gain of function of these miRNA controls the generation of Aβ independently of the changes in APP expression. Similar studies have examined the miRNAs regulating tau expression (miR-34 family) [140] and the proteins involved in the hyperphosphorylation of tau observed in AD (for example, miR-26b indirectly affects cytoplasmic export of cyclin-dependent kinase 5 (Cdk5), a major tau kinase [141]) (Fig. 3a).…”

Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases

“…To date, researchers found several miRNA-binding sites and they were able to validate direct inhibition of human tau by miR-34a [56]. Another approach to inhibit NFT formation is represented by regulating the phosphorylation status of tau protein.…”

How Does p73 Cause Neuronal Defects?

“…It was suggested that this effect on tau was predominantly due to a reduction in ΔNp73 isoform expression and was mediated through an effect on JNK [55]. The p73/miR-34a axis has also been implicated in AD, as high levels of TAp73 and miR-34a have been found in brains from both mouse models of AD and AD patients [120][121][122]56].…”