Abstract：
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.
摘要：
阿尔茨海默病(AD)和帕金森病(PD)导致显著的神经元丢失并严重损害日常生活。尽管临床表现不同，这些疾病具有共同的病理分子标志，包括线粒体功能障碍和突触变性。皮层中单细胞分辨率下分子变化的详细比较，作为受这两种疾病影响的主要大脑区域之一，可能揭示常见的易感因素和疾病机制。我们对AD和PD受试者和对照的死后皮质组织进行了单细胞转录组学分析，以确定单个基因中常见和不同的疾病相关变化。细胞通路，分子网络，和细胞间的通信事件，并调查共同机制。结果揭示了明显的疾病特异性，共享,和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。缺氧信号和脂质代谢在AD和PD中作为显著调节的细胞过程出现,这两种疾病之间有相反的表达改变。此外，通路和细胞-细胞通讯分析都强调了涉及JAK-STAT信号通路的共同重大改变，这与几种神经退行性疾病的炎症反应有关。总的来说,分析揭示了基因特征中常见和不同的改变，途径活动，以及AD和PD中的基因调控子网络。这些结果为通路活性和细胞间通讯的协调变化提供了见解，可以指导未来的诊断和治疗。
