Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function

Molecular Neurodegeneration

Sébastien S Hébert²  Paul Mathews¹  Frédéric Calon³  Charlotte Delay² 

[1] NYU School of Medicine, Nathan Kline Institute, Orangeburg (NY), USA;Université Laval, Faculté de médecine, Département de psychiatrie et de neurosciences, Québec (Qc), Canada;Université Laval, Faculté de pharmacie, Québec (Qc), Canada

关键词: miR-147, miR-20a;    Alzheimer's disease;    microRNA, single nucleotide polymorphism;    Amyloid precursor protein;   

Others  :  865570
DOI  :  10.1186/1750-1326-6-70

 received in 2011-05-09, accepted in 2011-10-07,  发布年份 2011

【 摘 要 】

Background

APP expression misregulation can cause genetic Alzheimer's disease (AD). Recent evidences support the hypothesis that polymorphisms located in microRNA (miRNA) target sites could influence the risk of developing neurodegenerative disorders such as Parkinson's disease (PD) and frontotemporal dementia. Recently, a number of single nucleotide polymorphisms (SNPs) located in the 3'UTR of APP have been found in AD patients with family history of dementia. Because miRNAs have previously been implicated in APP expression regulation, we set out to determine whether these polymorphisms could affect miRNA function and therefore APP levels.

Results

Bioinformatics analysis identified twelve putative miRNA bindings sites located in or near the APP 3'UTR variants T117C, A454G and A833C. Among those candidates, seven miRNAs, including miR-20a, miR-17, miR-147, miR-655, miR-323-3p, miR-644, and miR-153 could regulate APP expression in vitro and under physiological conditions in cells. Using luciferase-based assays, we could show that the T117C variant inhibited miR-147 binding, whereas the A454G variant increased miR-20a binding, consequently having opposite effects on APP expression.

Conclusions

Taken together, our results provide proof-of-principle that APP 3'UTR polymorphisms could affect AD risk through modulation of APP expression regulation, and set the stage for further association studies in genetic and sporadic AD.

【 授权许可】

   
2011 Delay et al; licensee BioMed Central Ltd.

【 图 表 】

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