O3‐02–07: Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways

小RNA 生物 神经发生 疾病 神经科学 生物信息学 医学 基因 病理 遗传学
作者
Jill Richardson,John Cogswell,James M. Ward,Ian A. Taylor,Michelle Waters,Yunling Shi,Brian D. Cannon,Kevin Kelnar,Jon Kemppainen,David Brown,Caifu Chen,Rab K. Prinjha,Ann M. Saunders,Allen D. Roses,Cynthia A. Richards
出处
期刊:Alzheimers & Dementia [Wiley]
卷期号:4 (4S_Part_5) 被引量:18
标识
DOI:10.1016/j.jalz.2008.05.420
摘要

Despite considerable progress in the development and validation of imaging and neuroelectrophysiological techniques, it remains difficult to conclusively diagnose Alzheimer's disease (AD) in its early stages. There is an urgent medical need to develop novel biomarkers to inform the diagnosis, development and testing of novel therapeutic agents. MicroRNAs (miRNAs) are small regulatory RNAs that bind the 3’ untranslated region (UTR) of target genes and inhibit their expression post-transcriptionally. MiRNAs are more stably expressed than mRNAs and miRNAs can also be detected in human fluids. MiRNAs have essential functional roles in brain development and neuronal specification but their role in neurodegenerative diseases such as AD is unknown. We sought to investigate whether miRNAs were differentially expressed in brain and CSF between AD and non-affected controls. The expression of over 300 miRNAs was determined in hippocampus, medial frontal gyrus, and cerebellum from early and late stage AD compared to age-matched controls. CSF miRNA profiling was performed using RT and pre-amplification modifications of the TaqMan™ miRNA Assays (Applied Biosystems). 313-plex RT mix and miRNA PreAmp primers were obtained from Applied Biosystems. We identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease. Our data provides the first genome scale description of miRNAs that are differentially expressed in Alzheimer's disease brain and importantly further demonstrates their presence and disease-altered expression in cerebrospinal fluid. Through experimental follow up and literature mining of miRNA targets we could establish that the identified miRNAs are useful biomarkers of known and novel pathways contributing to AD pathogenesis. The quantitative changes in expression we have seen in CSF suggest that miRNAs have the potential to provide accessible biomarkers to aid diagnosis of AD.
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