Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
J Neurochem. 2011 Mar;116(6):937-46. doi: 10.1111/j.1471-4159.2010.07157.x. Epub 2011 Jan 19.
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.
阿尔茨海默病（AD）在西方世界的患病率正在迅速上升，预计将对经济和社会产生重大影响。目前的治疗方法并不能改变潜在的疾病进程，因此需要新的治疗方法来避免这种即将到来的疾病流行。AD 的临床症状是由于皮质神经元大量丧失引起的。为了有效，神经保护策略需要在这种细胞丢失之前实施。然而，这需要发现临床前标志物来识别易感患者，以及早期的发病机制作为治疗靶点。尽管生物标志物和发病机制可能重叠，但可能需要新的方法来确定疾病的新元素。转录组分析，假设没有预先的病因假设，在阐明像 AD 这样的复杂疾病的发病机制方面有很大的希望。微阵列是转录组分析最流行的平台，并已应用于 AD 模型、患者样本和死后脑组织。这些研究的结果在很大程度上不一致，这在某种程度上可能反映了这种基于探针杂交的方法的局限性。相比之下，全转录组测序（RNA-Seq）利用高效、下一代 DNA 测序方法，具有改善的动态范围和转录检测范围。RNA-Seq 不仅非常适合对基因组复杂的人脑组织进行研究，而且可以克服神经退行性疾病死后脑组织病例对照比较中固有的技术问题。该平台产生的数据量很大，成为主要的后勤障碍，需要系统的实验方法来最大限度地检测与发病相关的信号。尽管如此，RNA-Seq 有望在我们对 AD 发病机制的理解上取得重大突破。
