Amyloid peptide exerts a rapid induction of Dicer1 protein in neuron via reducing phosphorylation

A growing number of evidence suggests that altered microRNA network in the brain contributes to the risk of Alzheimer's disease(AD). Dicer1 is a type III riboendonuclease which cleaves pre-microRNA into functional microRNA. Reduction of Dicer1 or Dicer1 mutation has been involved in cancer, aging or age-related macular degeneration. Recently, we found a possible link between Dicer1 and AD. In particular, Dicer1 protein and Dicer1 mRNA is reduced in the hippocampus and the cortex of an animal model of AD and exposure to A1342 oligomer (A13O) longer than 6 h reduces the transcription of Dicer1 gene in neuron, via depletion of NF-E2-related factor-2. In this study, exposure to A13O at shorter time increased Dicer1 protein in neuron in a dose-dependent mode; but the mRNA level remained unaltered. Under this treatment regime,A13O reduced phosphorylation level of Dicer1 and of its binding partner, transactivation response element RNA-binding protein(TRBP). Addition of a JNK inhibitor,SP600125, or an ERK inhibitor,U0126, further increased Dicer1 protein compared to A13o treatment alone, with simultaneaous reduction of phospho-Dicer1, but with different effects on phospho-TRBP. Finally, an inhibitor of calcineurin,FK506, further increased Dicer1 protein compared to A13o treatment alone. Thus, phosphorylation of Dicer1 and TRBP was determined by mitogen activated protein kinases JNK,ERK, and protein phosphatase 2B(calcineurin) which together determined Dicer1 stability. In summary, reduced phosphorylation of Dicer1 accounted for the rapid induction of Dicer1 by A13O. This study highlights a novel way by which A13O regulates Dicer1.

Automated summary

The study suggests a potential link between Dicer1 and Alzheimer's disease, showing that exposure to A13O can affect Dicer1 protein and mRNA levels in neurons. A13O regulates Dicer1 stability in neurons by influencing its phosphorylation level.