MicroRNA-101 Regulates Amyloid Precursor Protein Expression in Hippocampal Neurons

Carlo Cogoni,MariaTeresa Ciotti,Elisa Vilardo,Christian Barbato,Francesca Ruberti

doi:10.1074/jbc.m110.112664

Abstract

The amyloid precursor protein (APP) and its proteolytic product amyloid beta (Abeta) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3'-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and Abeta load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1beta (IL-lbeta). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Abeta, suggesting a possible role for miR-101 in neuropathological conditions.

Highlights

Tors of amyloid precursor protein (APP) expression [7,8] is the proinflammatory cytokine IL-1␤ [9]
MicroRNAs are an intriguing class of small noncoding RNA molecules which, in mammals, regulate gene expression primarily by imperfect base pairing with the 3Ј-untranslated region (UTR) of specific target mRNAs [19]
No significant alteration of APP mRNA was observed (Fig. 1D), suggesting that in hippocampal neurons APP translation may be regulated by an Ago2/ microRNA pathway

Summary

Introduction

Tors of APP expression [7,8] is the proinflammatory cytokine IL-1␤ [9]. IL-1␤ is produced in the central nervous system (CNS) in response to damage and influences neuronal function by interacting with the type I IL-1 receptor expressed on neurons (10 –11). We show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. We focused on identifying a microRNA regulating APP expression in primary cultures of rat hippocampal neurons.

Results

Conclusion