Characterizing dysregulations via cell-cell communications in Alzheimer’s brains using single-cell transcriptomes

Author:

Lee Che YuORCID,Riffle Dylan,Xiong Yifeng,Momtaz Nadia,Hwang AhyeonORCID,Duan ZihengORCID,Zhang Jing

Abstract

AbstractAlzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing (snRNA-seq) in the human prefrontal cortex (PFC) from 23 AD samples and 13 controls to investigate cell-to-cell communication (C2C) in healthy brains and their perturbations in AD. Specifically, we first performed broad communication pattern analyses and discovered the inter-mixing of cell types and signaling pathways in AD brains. Secondly, we performed cell-type- centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other supporting cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFβ, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and WNT pathway is dysregulated in its signaling from endothelial to neuronal cells in AD. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type- specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, connecting signaling to genetic differences manifested in AD.Author SummaryAlzheimer’s is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The complex interplay of signaling genes suggests cells act in concert with other cells through cell-to-cell communication. Utilizing the recent advances in single-cell sequencing, we investigated dysregulated ligand-receptor gene pairs in the disease at the cell-type resolution. Specifically, our broad communication pattern analyses revealed the inter-mixing of cell types and signaling pathways in AD brains. Our cell-type-centric analysis found that excitatory neurons in AD have significantly increased their communications with inhibitory neurons, while inhibitory neurons and other supporting cells globally decreased theirs to all cells. With a signaling-centric view, we show that CSF, TGFβ, and CX3C pathways are significantly dysregulated in their signaling to the cell type microglia/PVM while the WNT pathway is dysregulated in its signaling from endothelial to neuronal cells in AD. Finally, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. In summary, performing a cell-to-cell communication analysis better explains the genetic differences manifested in Alzheimer’s.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3