Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Biosciences, University of Exeter, Exeter, UK.
Nat Commun. 2024 Aug 2;15(1):6458. doi: 10.1038/s41467-024-50486-8.
Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.
越来越多的证据表明，可变剪接在阿尔茨海默病（AD）发病机制中发挥着重要作用。我们使用长读测序并结合一种新的生物信息学工具（FICLE），对携带人源 tau 突变体的雌性转基因（TG）小鼠的内嗅皮层中的转录本多样性进行了分析。我们的分析揭示了数百种新的异构体，并鉴定了差异表达的转录本，包括 Apoe、App、Cd33、Clu、Fyn 和 Trem2 的特定异构体，这些异构体与 TG 小鼠 tau 病理学的发展有关。随后对 AD 个体和对照者的人类皮层进行的分析显示，转录本多样性存在相似的模式，包括 AD 中 TREM2 优势异构体的上调，与 TG 小鼠中同源转录本表达增加相平行。我们的研究结果强调了差异转录本使用的重要性，即使在没有基因水平表达改变的情况下，它也是 AD 神经病理学发展中基因调控的一种机制。
