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J Neurochem. 2011 Mar;116(6):937-46. doi: 10.1111/j.1471-4159.2010.07157.x. Epub 2011 Jan 19.

Understanding the pathogenesis of Alzheimer's disease: will RNA-Seq realize the promise of transcriptomics?

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1
Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. g.sutherland@sydney.edu.au

Abstract

The prevalence of Alzheimer's disease (AD) is increasing rapidly in the western world and is poised to have a significant economic and societal impact. Current treatments do not alter the underlying disease processes meaning new treatments are required if this imminent epidemic is to be averted. The clinical manifestations of AD are secondary to a substantial loss of cortical neurons. To be effective, neuroprotective strategies will need to be implemented prior to this cell loss. However, this requires the discovery of both pre-clinical markers to identify susceptible patients and the early pathogenic mechanisms to serve as therapeutic targets. Although the biomarkers and pathogenic mechanisms may overlap, it is likely that new approaches are required to identify novel elements of the disease. Transcriptomic analyses, that assume no a priori etiological hypotheses, promise much in elucidating the pathogenesis of complex diseases like AD. Microarrays are the most popular platform for transcriptomic analysis and have been applied across AD models, patient samples and postmortem brain tissue. The results of these studies have been largely discordant which could, to some extent, reflect the limitations of this probe-hybridization-based methodology. In comparison, whole transcriptome sequencing (RNA-Seq) utilizes a highly efficient, next-generation DNA sequencing method with improved dynamic range and scope of transcript detection. RNA-Seq is not only highly suited to investigations of the genomically complex human brain tissue but it can potentially overcome technical issues inherent to case-control comparisons of postmortem brain tissue in neurodegenerative diseases. The volume of data generated by this platform looms as the major logistical hurdle and a systematic experimental approach will be required to maximise the detection of pathogenically relevant signals. Nevertheless, RNA-Seq looks set to deliver a quantum leap forward in our understanding of AD pathogenesis.

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