Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder.
Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder.
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DOI：
10.1186/s12974-021-02204-0
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发表时间：
2021-07-08
影响因子：
9.3
通讯作者：
Trazzi S
中科院分区：
文献类型：
--
作者：
Galvani G;Mottolese N;Gennaccaro L;Loi M;Medici G;Tassinari M;Fuchs C;Ciani E;Trazzi S
CDKL 5缺乏症（CDD）是一种严重的神经发育障碍，其特征是早发性癫痫、智力残疾和自闭症特征，由CDKL 5基因突变引起。CDD动物模型中的证据表明，CDKL 5的缺乏会对神经元存活以及神经元成熟和树突状生长产生负面影响;然而，对这些改变背后的底物的了解仍然有限。已知神经炎症过程导致神经元功能障碍和死亡。最近的证据显示，CDD患者血浆中存在亚临床慢性炎症状态。然而，迄今为止，尚不清楚CDD患者的大脑中是否存在类似的炎症状态，如果存在，则这是否在CDD的病理生理学中起致病或加重作用。我们使用AIF-1免疫荧光、促炎细胞因子表达和CDD小鼠模型（Cdkl 5 KO小鼠）脑中的信号传导评估了小胶质细胞活化，其特征在于海马神经元的存活受损，并随年龄增长而增加。通过DCX、NeuN和裂解的半胱天冬酶-3免疫染色在用木犀草素（10 mg/kg）（一种天然抗炎类黄酮）处理的Cdkl 5 KO小鼠中测定海马神经元存活。由于Cdkl 5 KO小鼠的海马神经元表现出对兴奋性毒性应激的敏感性增加，我们评估了用木犀草素治疗7天后注射NMDA（60 mg/kg）的Cdkl 5 KO小鼠中的神经元存活。我们发现Cdkl 5 KO小鼠脑中的小胶质细胞活化增加。我们发现小胶质细胞形态和数量的改变，AIF-1和促炎细胞因子水平的增加，以及STAT 3信号的激活。值得注意的是，用毛地黄黄酮治疗恢复Cdkl 5 KO小鼠中的小胶质细胞改变以及神经元存活和成熟，并防止海马中NMDA诱导的细胞死亡增加。我们的研究结果表明，神经炎症过程有助于CDD的发病机制，并暗示毛地黄黄酮作为CDD患者的治疗选择的潜在有用性。在线版本包含补充材料，可通过10.1186/s12974-021-02204-0获得。
CDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in the CDKL5 gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD. We evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression, and signaling in the brain of a mouse model of CDD, the Cdkl5 KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN, and cleaved caspase-3 immunostaining in Cdkl5 KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons of Cdkl5 KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival in Cdkl5 KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin. We found increased microglial activation in the brain of the Cdkl5 KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation in Cdkl5 KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus. Our results suggest that neuroinflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients. The online version contains supplementary material available at 10.1186/s12974-021-02204-0.
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影响因子：
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