Zaman Masihuz, Yang Shu, Huang Ya, Yarbro Jay M, Hao Yanhong, Wang Zhen, Liu Danting, Harper Kiara E, Soliman Hadeer, Hemphill Alex, Harvey Sarah, Pruett-Miller Shondra M, Stewart Valerie, Tanwar Ajay Singh, Kalathur Ravi, Grace Christy R, Turk Martin, Chittori Sagar, Jiao Yun, Wu Zhiping, High Anthony A, Wang Xusheng, Serrano Geidy E, Beach Thomas G, Yu Gang, Yang Yang, Chen Ping-Chung, Peng Junmin
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
bioRxiv. 2025 Mar 20:2025.03.20.644383. doi: 10.1101/2025.03.20.644383.
Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with Aβ since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimer's disease.
阿尔茨海默病（AD）大脑的蛋白质组分析已鉴定出许多研究不足的蛋白质，包括中期因子（MDK），自疾病早期阶段以来，这些蛋白质高度上调且与Aβ相关，但它们在疾病进展中的作用尚未完全了解。在此，我们展示了MDK在5xFAD淀粉样变性小鼠模型中可减弱Aβ组装并影响淀粉样蛋白形成。在硫黄素T荧光测定、圆二色性、负染电子显微镜和核磁共振分析中，MDK蛋白可减轻Aβ40和Aβ42肽的纤维形成。在5xFAD中敲除该基因会增加淀粉样蛋白形成和小胶质细胞活化。对这些小鼠模型中全蛋白质组和去污剂不溶性蛋白质组进行基于质谱的进一步全面分析表明，Aβ和Aβ相关蛋白以及小胶质细胞成分显著积累。因此，我们的结构和小鼠模型研究揭示了MDK在对抗阿尔茨海默病淀粉样病理中的保护作用。
