细胞串扰的系统分析揭示了SEMA6D-TREM2在阿尔茨海默病中调节小胶质细胞功能的作用

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Ricardo D’Oliveira Albanus, Gina M. Finan, Logan Brase, Nicholas Sweeney, Tae Yeon Kim, Shuo Chen, Yeonsu Ryoo, Joseph Park, Qi Guo, Abhirami Kannan, Mariana Acquarone, Shih-Feng You, Brenna C. Novotny, Emily M. Mace, Patricia M. Ribeiro Pereira, John C. Morris, David M. Holtzman, Eric McDade, Martin Farlow, Jasmeer P. Chhatwal, Bruno A. Benitez, Laura Piccio, Richard J. Perrin, Greg T. Sutherland, Qin Ma, Celeste M. Karch, Doo Yeon Kim, Rudolph E. Tanzi, Hongjun Fu, Oscar Harari, Tae-Wan Kim
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引用次数: 0

摘要

由膜受体及其配体介导的细胞串扰对大脑稳态至关重要,并可能导致阿尔茨海默病(AD)等神经退行性疾病。为了发现与阿尔茨海默病相关的串音失调,我们从Knight阿尔茨海默病研究中心和显性遗传阿尔茨海默病网络队列中67名临床和神经病理学特征良好的对照和阿尔茨海默病脑供者的单核转录谱中重建了串音网络。我们预测了TREM2和其他AD风险基因在AD中介导神经元-小胶质细胞串导的作用。我们发现了一个通过TREM2和神经元SEMA6D介导神经元-小胶质细胞串扰的基因网络,我们预测该基因网络在阿尔茨海默病晚期被破坏。利用人脑空间转录组学,我们观察到SEMA6D-TREM2串扰基因网络在Aβ斑块和表达sema6d的细胞附近被激活。利用人脑组织免疫染色,我们发现SEMA6D与Aβ斑块和trem2激活的小胶质细胞共定位。此外,我们发现斑块近端SEMA6D丰度随着疾病分期而降低,这与斑块附近小胶质细胞激活的减少有关。这些发现表明,SEMA6D信号的缺失会损害小胶质细胞的激活和Αβ清除。为了验证这一假设,我们利用TREM2敲除人类诱导的多能干细胞来源的小胶质细胞,观察到SEMA6D以TREM2依赖的方式诱导小胶质细胞激活和a β斑块吞噬。总之,我们证明了细胞串扰网络的特征可以深入了解阿尔茨海默病生物学,为了解阿尔茨海默病遗传风险提供额外的背景,并发现以前未知的治疗靶点和途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease
Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged TREM2 knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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