阿尔茨海默病细胞间通讯变化分析揭示小鼠和人类谷氨酸能传递的保守变化。

Analysis of changes in intercellular communications in Alzheimer's disease reveals conserved changes in glutamatergic transmission in mice and humans.

作者信息

Bartas Katrina, Nguyen Megan, Zhao Wei, Hui May, Nie Qing, Beier Kevin T

机构信息

Program in Mathematical, Computational, and Systems Biology, University of California, Irvine, Irvine, CA, 92617, USA.

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, 92617, USA.

出版信息

Sci Rep. 2025 Jul 19;15(1):26248. doi: 10.1038/s41598-025-10795-4.

DOI:10.1038/s41598-025-10795-4

PMID:40683902

Abstract

Analysis of system-wide cellular communication changes in Alzheimer's disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of people with AD and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and people with AD.

摘要

最近，单核RNA测序（snRNA-seq）和新的计算方法使得对阿尔茨海默病（AD）全系统细胞通讯变化的分析成为可能。在这里，我们结合这些方法，分析了AD患者内嗅皮质的死后人体组织数据，并将我们的发现与5xFAD淀粉样蛋白生成小鼠模型在两个不同时间点的多组学数据进行了比较。使用细胞通讯推断工具CellChat，我们发现疾病相关变化主要与神经元兴奋性以及突触通讯有关，特定的信号通路包括骨形态发生蛋白（BMP）、表皮生长因子（EGF）和EPH受体A（EPHA），并且在疾病过程中与胶质细胞相关的变化保守性相对较差。使用神经元特异性的NeuronChat进行的进一步分析揭示了与代谢型谷氨酸受体以及包括神经连接蛋白和神经配体在内的神经元粘附分子相关的变化。我们的结果表明，与兴奋性毒性相关的细胞过程在5xFAD小鼠和AD之间保守性最好，这表明兴奋性毒性是5xFAD小鼠和AD患者发病机制之间的主要共同特征。