Department of Medical Biochemistry and Biophysics , Umeå University , Umeå SE-90187 , Sweden.
Department of General Chemistry , Sumy State University , Sumy 40007 , Ukraine.
ACS Chem Neurosci. 2018 Jun 20;9(6):1338-1348. doi: 10.1021/acschemneuro.7b00512. Epub 2018 Apr 12.
Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Bax, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the S100A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and S100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes.
淀粉样蛋白形成和神经炎症是阿尔茨海默病病理学的主要特征。促炎介质 S100A9 被证明是阿尔茨海默病中淀粉样蛋白和神经炎症级联之间的联系，与 Aβ 一起导致斑块形成、神经元丢失和记忆障碍。为了研究 S100A9 自身在天然状态和淀粉样状态下是否可以单独诱导神经元应激和记忆障碍，我们将 S100A9 物种经鼻腔给予老年小鼠。进行了单次和顺序免疫组织化学和被动回避行为测试以评估后果。给予 S100A9 物种会在大脑结构中引起广泛的细胞应激反应，包括额叶、海马体和小脑。这表现为 S100A9、Bax 的水平增加，并且激活的 caspase-3 免疫阳性细胞较少。在给予 S100A9 原纤维后，观察到脑组织中的淀粉样寡聚体形成，这会进一步加剧细胞应激。细胞应激反应与在被动回避测试中观察到的 S100A9 处理动物组的训练时间显著增加和保留时间显著减少相关。值得注意的是，在接受天然 S100A9 治疗的组中，行为测试的效应大小已经适中，而在给予 S100A9 淀粉样寡聚体或原纤维的组中，效应大小较大。这些发现表明 S100A9 物种对大脑易受神经毒性损伤的敏感性导致行为和记忆障碍。S100A9 物种的鼻腔给药被证明是研究淀粉样蛋白诱导的大脑功能障碍的有效方法，并且 S100A9 本身可以被假定为减轻早期神经退行性和神经炎症过程的靶点。
