Differential transcript usage unravels gene expression alterations in Alzheimer's disease human brains.

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
Diego Marques-Coelho, Lukas da Cruz Carvalho Iohan, Ana Raquel Melo de Farias, Amandine Flaig, Jean-Charles Lambert, Marcos Romualdo Costa
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引用次数: 47

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.

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差异转录物的使用揭示了阿尔茨海默病人类大脑中的基因表达改变。
阿尔茨海默病(AD)是老年人痴呆症的主要原因。然而,阿尔茨海默病发病和进展的病理生理过程仍然知之甚少。在众多策略中,对患病大脑中基因表达改变的全面概述可能有助于更好地了解AD的病理。在这项工作中,我们利用来自梅奥诊所、西奈山脑库(MSBB)和ROSMAP三个大型转录组学研究的数据,探讨了健康和AD成人受试者不同脑区基因的差异表达。结合基因差异表达和异构体开关分析,我们提供了阿尔茨海默病早期和晚期受影响的颞叶和额叶大脑区域基因表达改变的详细图景。接下来,我们利用间接方法将大量RNAseq中揭示的复杂基因表达变化分配给成人大脑的单个细胞类型/亚型。这种策略使我们能够识别以前被忽视的阿尔茨海默病患者大脑中的基因表达变化。在这些改变中,我们发现了阿尔茨海默病致病基因淀粉样蛋白- β前体蛋白(APP)和风险基因桥接整合子1 (BIN1)的异构体开关,这可能在神经元细胞中具有重要的功能后果。总之,我们的工作提出了一种新的综合策略,基于基因/转录物表达和区域/细胞类型特异性来分析AD和其他神经退行性疾病中的RNAseq数据。
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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
发文量
0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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