PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) presents a complex interplay of molecular alterations, yet understanding its pathogenesis remains a challenge. In this study, we delved into the intricate landscape of proteome and transcriptome changes in AD brains compared to healthy controls, examining 788 brain samples revealing common alterations at both protein and mRNA levels. Moreover, our analysis revealed distinct protein-level changes in aberrant energy metabolism pathways in AD brains that were not evident at the mRNA level. This suggests that the changes in protein expression could provide a deeper molecular representation of AD pathogenesis. Subsequently, using a comparative proteomic approach, we explored the therapeutic potential of mesenchymal stem cell-derived extracellular vehicles (EVs), isolated through various methods, in mitigating AD-associated changes at the protein level. Our analysis revealed a particular EV-subtype that can be utilized for compensating dysregulated mitochondrial proteostasis in the AD brain. By using network biology approaches, we further revealed the potential regulators of key therapeutic proteins. Overall, our study illuminates the significance of proteome alterations in AD pathogenesis and identifies the therapeutic promise of a specific EV subpopulation with reduced pro-inflammatory protein cargo and enriched proteins to target mitochondrial proteostasis.
摘要：
阿尔茨海默病(AD)呈现出分子改变的复杂相互作用，然而，了解其发病机制仍然是一个挑战。在这项研究中,与健康对照相比，我们深入研究了AD大脑中蛋白质组和转录组变化的复杂图景，检查788个大脑样本，揭示蛋白质和mRNA水平的常见变化。此外，我们的分析揭示了AD大脑中异常能量代谢途径中蛋白质水平的明显变化,这在mRNA水平上并不明显.这表明蛋白质表达的变化可以为AD发病机理提供更深层次的分子代表。随后，使用比较蛋白质组学方法，我们探索了间充质干细胞衍生的细胞外载体（EV）的治疗潜力，通过各种方法隔离，减轻蛋白质水平的AD相关变化。我们的分析揭示了一种特定的EV亚型，可用于补偿AD脑中线粒体蛋白质失调。通过使用网络生物学方法，我们进一步揭示了关键治疗蛋白的潜在调节因子.总的来说,我们的研究阐明了蛋白质组改变在AD发病机制中的意义，并确定了特定EV亚群的治疗前景，该亚群具有减少的促炎蛋白负荷和富含靶向线粒体蛋白质的蛋白质。
