Le Bars Sophie, Glaab Enrico
Biomedical Data Science Group, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Mol Neurobiol. 2025 Mar;62(3):2655-2673. doi: 10.1007/s12035-024-04419-7. Epub 2024 Aug 15.
Alzheimer's disease (AD) and Parkinson's disease (PD) cause significant neuronal loss and severely impair daily living. Despite different clinical manifestations, these disorders share common pathological molecular hallmarks, including mitochondrial dysfunction and synaptic degeneration. A detailed comparison of molecular changes at single-cell resolution in the cortex, as one of the main brain regions affected in both disorders, may reveal common susceptibility factors and disease mechanisms. We performed single-cell transcriptomic analyses of post-mortem cortical tissue from AD and PD subjects and controls to identify common and distinct disease-associated changes in individual genes, cellular pathways, molecular networks, and cell-cell communication events, and to investigate common mechanisms. The results revealed significant disease-specific, shared, and opposing gene expression changes, including cell type-specific signatures for both diseases. Hypoxia signaling and lipid metabolism emerged as significantly modulated cellular processes in both AD and PD, with contrasting expression alterations between the two diseases. Furthermore, both pathway and cell-cell communication analyses highlighted shared significant alterations involving the JAK-STAT signaling pathway, which has been implicated in the inflammatory response in several neurodegenerative disorders. Overall, the analyses revealed common and distinct alterations in gene signatures, pathway activities, and gene regulatory subnetworks in AD and PD. The results provide insights into coordinated changes in pathway activity and cell-cell communication that may guide future diagnostics and therapeutics.
阿尔茨海默病（AD）和帕金森病（PD）会导致大量神经元丧失，并严重损害日常生活。尽管临床表现不同，但这些疾病具有共同的病理分子特征，包括线粒体功能障碍和突触退化。作为这两种疾病中均受影响的主要脑区之一，对皮质单细胞分辨率下的分子变化进行详细比较，可能会揭示共同的易感因素和疾病机制。我们对来自AD、PD受试者及对照的死后皮质组织进行了单细胞转录组分析，以确定个体基因、细胞通路、分子网络和细胞间通讯事件中与疾病相关的共同和不同变化，并研究共同机制。结果揭示了显著的疾病特异性、共享性及相反的基因表达变化，包括两种疾病的细胞类型特异性特征。缺氧信号传导和脂质代谢在AD和PD中均表现为显著受调控的细胞过程，且两种疾病之间存在相反的表达改变。此外，通路分析和细胞间通讯分析均突出了涉及JAK-STAT信号通路的共享显著改变，该通路在几种神经退行性疾病的炎症反应中发挥作用。总体而言，这些分析揭示了AD和PD在基因特征、通路活性和基因调控子网方面的共同和不同改变。研究结果为通路活性和细胞间通讯的协同变化提供了见解，可能会为未来的诊断和治疗提供指导。
