Abstract
Although microRNAs are being extensively studied for their involvement in cancer and development, little is known about their roles in Alzheimer's disease (AD). In this study, we used microarrays for the first joint profiling and analysis of miRNAs and mRNAs expression in brain cortex from AD and age-matched control subjects. These data provided the unique opportunity to study the relationship between miRNA and mRNA expression in normal and AD brains. Using a non-parametric analysis, we showed that the levels of many miRNAs can be either positively or negatively correlated with those of their target mRNAs. Comparative analysis with independent cancer datasets showed that such miRNA-mRNA expression correlations are not static, but rather context-dependent. Subsequently, we identified a large set of miRNA-mRNA associations that are changed in AD versus control, highlighting AD-specific changes in the miRNA regulatory system. Our results demonstrate a robust relationship between the levels of miRNAs and those of their targets in the brain. This has implications in the study of the molecular pathology of AD, as well as miRNA biology in general.
Highlights
Neurodegeneration and dementia in Alzheimer’s disease (AD) are associated with neurotoxicity of the amyloid-beta peptide, which accumulates as amyloid fibrils in senile plaques characteristic of AD, and as oligomers that directly bind to neurons [1,2,3]
Expressed miRNAs and mRNAs Total RNA was extracted from the parietal lobe cortex of 10 individuals (5 AD patients and 5 age-matched control subjects)
After RNA quality control, only 8 samples (4 from each group) were used in the final study. These are too few to draw any reliable conclusions about differential expression of hundreds of miRNAs and mRNAs, we briefly present that analysis for completeness and as a resource for future meta-analyses
Summary
Neurodegeneration and dementia in Alzheimer’s disease (AD) are associated with neurotoxicity of the amyloid-beta peptide, which accumulates as amyloid fibrils in senile plaques characteristic of AD, and as oligomers that directly bind to neurons [1,2,3]. A major clue was given by Down’s syndrome, in which trisomy of chromosome 21 results in early onset of AD, but not in a case in which chromosome 21 had a mosaic deletion of the amyloid precursor protein (APP) locus [4]. This evidence highlighting the importance of gene dosage in AD is one of the rationales for the study of gene expression in AD brain. Among the few RNA changes that are shared among expression studies, there is no clear functional relationship. A future challenge is to integrate large amounts of data in a network context, for which studies such as OSCAR [6] may be a useful model
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