阿尔茨海默病遗传型和散发型的空间及单核转录组分析

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's Disease.

作者信息

Miyoshi Emily, Morabito Samuel, Henningfield Caden M, Rahimzadeh Negin, Kiani Shabestari Sepideh, Das Sudeshna, Michael Neethu, Reese Fairlie, Shi Zechuan, Cao Zhenkun, Scarfone Vanessa, Arreola Miguel A, Lu Jackie, Wright Sierra, Silva Justine, Leavy Kelsey, Lott Ira T, Doran Eric, Yong William H, Shahin Saba, Perez-Rosendahl Mari, Head Elizabeth, Green Kim N, Swarup Vivek

机构信息

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.

Institute for Memory Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA.

出版信息

bioRxiv. 2023 Jul 26:2023.07.24.550282. doi: 10.1101/2023.07.24.550282.

DOI:10.1101/2023.07.24.550282

PMID:37546983

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10402031/

Abstract

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcriptomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in Down Syndrome (AD in DS) donors. Studying AD in DS provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. Our analysis revealed spatial and cell-type specific changes in disease, with broad similarities in these changes between sAD and AD in DS. We performed additional ST experiments in a disease timecourse of 5xFAD and wildtype mice to facilitate cross-species comparisons. Finally, amyloid plaque and fibril imaging in the same tissue samples used for ST enabled us to directly link changes in gene expression with accumulation and spread of pathology.

摘要

阿尔茨海默病（AD）的发病机制取决于环境和遗传因素，在分子水平上个体之间存在显著差异。在此，我们利用空间转录组学（ST）和单核RNA测序对来自早期AD、晚期AD和唐氏综合征（DS）患者的皮质样本进行转录组学研究。对DS患者的AD研究为深入了解AD转录组提供了机会，可能弥合基因小鼠模型与散发性AD之间的差距。我们的分析揭示了疾病中的空间和细胞类型特异性变化，散发性AD（sAD）和DS患者的AD在这些变化上具有广泛的相似性。我们在5xFAD和野生型小鼠的疾病时间进程中进行了额外的ST实验，以促进跨物种比较。最后，对用于ST的相同组织样本进行淀粉样斑块和纤维成像，使我们能够直接将基因表达变化与病理积累和扩散联系起来。