Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β-/- Mice, A Model of Adult Neuron Disease
Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β-/- Mice, A Model of Adult Neuron Disease
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DOI：
10.1097/nen.0b013e3181df20e1
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发表时间：
2010-06-01
影响因子：
3.2
通讯作者：
Gustafsson, Jan-Ake
中科院分区：
文献类型：
--
作者：
Bigini, Paolo;Steffensen, Knut R.;Gustafsson, Jan-Ake
在肌萎缩侧索硬化症（ALS）中，运动神经元发生选择性变性，导致瘫痪和死亡。虽然ALS的病因尚不清楚，但其异质性表明多种因素（内源性和/或环境）的组合可能诱导进行性运动神经元应激，导致不同细胞死亡途径的激活。脑胆固醇稳态的改变最近被认为是许多神经退行性疾病（包括ALS）的可能辅助因子。肝脏X受体β（LXR β）受体参与脂肪生成和胆固醇代谢，我们以前发现LXR β（-/-）小鼠中发生成人发病运动神经元病理学。在这里，我们研究了LXR β（-/-）小鼠从3到24个月的神经肌肉变化。胆固醇水平升高、神经胶质增生和炎症先于运动神经元丧失和临床疾病发作;小鼠从7个月大开始表现出进行性运动神经元缺陷。在24个月大的小鼠中，运动神经元和神经肌肉接头的数量减少，但没有观察到瘫痪或寿命缩短。此外，其他脊髓神经元也在这些小鼠中丢失。这些结果表明，LXR β可以抑制神经炎症和维持胆固醇稳态，并且LXR β（-/-）代表了研究胆固醇在ALS和其他神经退行性疾病中的作用的潜在模型。
In amyotrophic lateral sclerosis (ALS), there is selective degeneration of motor neurons that leads to paralysis and death. Although the etiology of ALS is unclear, its heterogeneity suggests that a combination of factors (endogenous and/or environmental) may induce progressive motor neuron stress that results in the activation of different cell death pathways. Alterations of brain cholesterol homeostasis have recently been considered as possible cofactors in many neurodegenerative disorders, including ALS. The liver X receptor beta (LXR beta) receptor is involved in lipogenesis and cholesterol metabolism, and we previously found that adult-onset motor neuron pathology occurs in LXR beta(-/-) mice. Here, we investigated neuromuscular alterations of LXR beta(-/-) mice from ages 3 to 24 months. Increased cholesterol levels, gliosis, and inflammation preceded motor neuron loss and clinical disease onset; the mice showed progressive motor neuron deficits starting from age 7 months. The numbers of motor neurons and neuromuscular junctions were decreased in 24-month-old mice, but neither paralysis nor reduced life span was observed. Moreover, other spinal neurons were also lost in these mice. These results suggest that LXR beta may inhibit neuroinflammation and maintain cholesterol homeostasis, and that LXR beta(-/-) represent a potential model for investigating the role of cholesterol in ALS and other neurodegenerative disorders.