Panayi Nicholas, Schulz Philip, He Ping, Hanna Brandon, Lifshitz Jonathan, Rowe Rachel, Sierks Michael R
Arizona State University.
University of Arizona College of Pharmacy: The University of Arizona College of Medicine Phoenix.
Res Sq. 2023 May 5:rs.3.rs-2865501. doi: 10.21203/rs.3.rs-2865501/v1.
Traumatic brain injury (TBI) increases the long-term risk of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we demonstrate that protein variant pathology generated in brain tissue of an experimental TBI mouse model is similar to protein variant pathology observed in human ADbrains, and that subacute accumulation of two AD associated variants of amyloid beta (Aβ) and tau in the TBI mouse model correlated with behavioral deficits. Male C57BL/6 mice were subjected to midline fluid percussion injury or to sham injury, after which sensorimotor function (rotarod, neurological severity score), cognitive deficit (novel object recognition), and affective deficits (elevated plus maze, forced swim task) were assessed at different days post-injury (DPI). Protein pathology at 7, 14, and 28 DPI was measured in multiple brain regions using an immunostain panel of reagents selectively targeting different neurodegenerative disease-related variants of Aβ, tau, TDP-43, and alpha-synuclein. Overall, TBI resulted in sensorimotor deficits and accumulation of AD-related protein variant pathology near the impact site, both of which returned to sham levels by 14 DPI. Individual mice, however, showed persistent behavioral deficits and/or accumulation of selected toxic protein variants at 28 DPI. Behavioral outcomes of each mouse were correlated with levels of seven different protein variants in ten brain regions at specific DPI. Out of 21 significant correlations between protein variant levels and behavioral deficits, 18 were with variants of Aβ or tau. Correlations at 28 DPI were all between a single Aβ or tau variant, both of which are strongly associated with human AD cases. These data provide a direct mechanistic link between protein pathology resulting from TBI and the hallmarks of AD.
创伤性脑损伤（TBI）会增加包括阿尔茨海默病（AD）在内的神经退行性疾病的长期风险。在此，我们证明了实验性TBI小鼠模型脑组织中产生的蛋白质变体病理学与人类AD大脑中观察到的蛋白质变体病理学相似，并且TBI小鼠模型中淀粉样β蛋白（Aβ）和tau蛋白的两种AD相关变体的亚急性积累与行为缺陷相关。雄性C57BL/6小鼠接受中线流体冲击损伤或假损伤，之后在损伤后不同天数（DPI）评估感觉运动功能（转棒试验、神经严重程度评分）、认知缺陷（新物体识别）和情感缺陷（高架十字迷宫、强迫游泳试验）。使用一组选择性靶向Aβ、tau、TDP-43和α-突触核蛋白不同神经退行性疾病相关变体试剂的免疫染色，在多个脑区测量7、14和28 DPI时的蛋白质病理学。总体而言，TBI导致感觉运动缺陷以及撞击部位附近AD相关蛋白质变体病理学的积累，两者在14 DPI时均恢复到假手术水平。然而，个别小鼠在28 DPI时表现出持续的行为缺陷和/或选定有毒蛋白质变体的积累。每只小鼠的行为结果与特定DPI时十个脑区中七种不同蛋白质变体的水平相关。在蛋白质变体水平与行为缺陷之间的21个显著相关性中，18个与Aβ或tau的变体相关。28 DPI时的相关性均为单一Aβ或tau变体之间的相关性，这两种变体均与人类AD病例密切相关。这些数据提供了TBI导致的蛋白质病理学与AD特征之间的直接机制联系。
