Abstract
A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs.
Highlights
amyloid precursor protein gene (APP) levels can be regulated at the genomic, transcriptional or translational level
Accumulating evidence suggests that increased expression of the amyloid precursor protein gene (APP) increases Alzheimer's disease (AD) risk
Dysregulation of APP transcription can increase the risk of AD
Summary
APP levels can be regulated at the genomic, transcriptional or translational level. At the genomic level, Down's Syndrome (Trisomy 21) patients have three copies of the APP gene and develop AD symptoms early in life [1]. To determine if the putative mir-106a target site in the APP 3'UTR is capable of regulating gene expression, we cloned it into the 3' UTR of firefly luciferase.
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