Trofimov Alexander, Pavlov Dmitrii, Goswami Anand, Gorlova Anna, Chaprov Kirill, Umriukhin Aleksei, Kalueff Allan, Deykin Alexey, Lesch Klaus-Peter, Anthony Daniel Clive, Strekalova Tatyana
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, the Netherlands.
Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Brain Behav Immun Health. 2023 Sep 15;33:100686. doi: 10.1016/j.bbih.2023.100686. eCollection 2023 Nov.
CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1-359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1-359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1-359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1-359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1-359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.
已知中枢神经系统炎症，包括小胶质细胞激活，是对周围感染的反应，这会导致家族性和散发性神经退行性疾病的病理变化。在转基因FUS[1-359]动物中，融合肉瘤蛋白（FUS）介导的疾病与全身炎症反应之间的关系尚未得到探索。在这里，我们研究了FUS[1-359]转基因小鼠中脂多糖诱导（LPS；0.1mg/kg）的全身炎症反应下的小胶质细胞激活、炎症基因表达和行为反应。这些小鼠的病理学概括了突变型FUS相关的家族性额颞叶痴呆（FTLD）和肌萎缩侧索硬化症（ALS）的关键特征。在这里，对无症状的8周龄突变型或野生型对照小鼠进行LPS或生理盐水刺激，并分析其蔗糖摄入量、新笼探索、埋大理石和游泳行为。还测定了促炎基因表达水平，并评估了小胶质细胞激活情况。在慢性实验中，为了发现LPS刺激是否会影响ALS样麻痹的发作，在注射后5至7周对动物的临床症状进行评估。与对照组相比，急性刺激的FUS[1-359]-tg小鼠表现出蔗糖摄入量减少和漂浮行为增加。FUS[1-359]-tg小鼠前额叶皮质和脊髓腹角中Iba1阳性细胞的免疫反应性增加，同时伴有白细胞介素-1β、肿瘤坏死因子、环氧化酶-（COX）-1和COX-2表达增加。然而，单次LPS刺激并没有改变FUS[1-359]-tg小鼠发生麻痹的时间。因此，虽然FUS突变动物的急性炎症反应增强，但它对疾病进展没有持久影响。
