Influence of Alzheimer's Disease Related Neuropathology on Local Microenvironment Gene Expression in the Human Inferior Temporal Cortex

IF 2 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Sang Ho Kwon, Sowmya Parthiban, Madhavi Tippani, Heena R. Divecha, Nicholas J. Eagles, Jashandeep S. Lobana, Stephen R. Williams, Michelle Mak, Rahul A. Bharadwaj, Joel E. Kleinman, Thomas M. Hyde, Stephanie C. Page, Stephanie C. Hicks, Keri Martinowich, Kristen R. Maynard, Leonardo Collado-Torres
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Abstract

Neuropathological lesions in the brains of individuals affected with neurodegenerative disorders are hypothesized to trigger molecular and cellular processes that disturb the homeostasis of local microenvironments. Here, we applied the 10x Genomics Visium Spatial Proteogenomics (Visium-SPG) platform, which couples spatial gene expression with immunofluorescence (IF) protein co-detection, to evaluate its ability to quantify changes in spatial gene expression with respect to amyloid-beta (Aβ) and hyperphosphorylated tau (pTau) pathology in post-mortem human brain tissue from individuals with Alzheimer's disease (AD). We identified transcriptomic signatures associated with proximity to Aβ in the human inferior temporal cortex during late-stage AD, which we further investigated at cellular resolution with combined IF and single-molecule fluorescent in situ hybridization (smFISH). The study provides a data analysis workflow for Visium-SPG, and the data represent a proof-of-principle for the power of multi-omic profiling in identifying changes in molecular dynamics that are spatially associated with pathology in the human brain. We provide the scientific community with web-based, interactive resources to access the datasets of the spatially resolved AD-related transcriptomes.
阿尔茨海默病相关神经病理对人类下颞叶皮层局部微环境基因表达的影响
神经退行性疾病患者大脑中的神经病理病变被认为会触发扰乱局部微环境稳态的分子和细胞过程。在这里,我们应用10x Genomics Visium Spatial Proteogenomics (Visium- spg)平台,该平台将空间基因表达与免疫荧光(IF)蛋白联合检测相结合,以评估其量化阿尔茨海默病(AD)患者死后脑组织中淀粉样蛋白- β (Aβ)和过度磷酸化tau (pTau)病理的空间基因表达变化的能力。我们在晚期阿尔茨海默病的人类下颞叶皮层中发现了与Aβ接近相关的转录组特征,并利用IF和单分子荧光原位杂交(smFISH)在细胞分辨率上进一步研究了这些特征。该研究为Visium-SPG提供了一个数据分析工作流程,这些数据代表了多组学分析在识别与人类大脑病理在空间上相关的分子动力学变化方面的能力的原理证明。我们为科学界提供基于网络的交互式资源,以访问空间解析ad相关转录组的数据集。
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