Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation
Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation
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DOI：
10.1016/j.nbd.2010.05.014
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发表时间：
2010-09-01
影响因子：
6.1
通讯作者：
Mena, Maria A.
中科院分区：
文献类型：
--
作者：
Rodriguez-Navarro, Jose A.;Rodriguez, Laura;Mena, Maria A.
tau蛋白病是散发性或家族性的神经退行性疾病，主要特征为与额颞皮质和基底神经节萎缩相关的痴呆和帕金森综合征，伴有脑中异常tau蛋白的沉积。遗传性tau蛋白病与tau基因突变有关。我们已经开发并表征了具有帕金森综合征的tau蛋白病的小鼠模型，其过表达具有parkin缺失的人突变tau蛋白（PK-/-/Tau（VLW））。在3个月大时，这些小鼠表现出异常的多巴胺相关行为、腹侧中脑中多巴胺神经元的严重缺失、纹状体中多巴胺水平降低和大量磷酸化tau阳性神经炎斑块、神经元缠结、星形胶质细胞增生，并且在12个月大时，鼠β-海藻糖是一种天然的二糖，通过增强自噬来增加异常蛋白质的去除。在这项工作中，我们测试了饮用水中1%的海藻糖是否会逆转PK-/-/Tau（VLW）表型。用海藻糖处理3月龄PK-/-/Tau（VLW）小鼠2.5个月，恢复了多巴胺神经元的脱落，这发生在溶媒处理的PK-/-/Tau（VLW）的腹侧中脑中，并降低了中脑和纹状体中的多巴胺相关蛋白水平。磷酸化tau蛋白阳性神经炎斑块的数量和磷酸化tau蛋白的水平降低，以及脑区域的星形胶质细胞增生。脑中的自噬标记物、从肝脏分离的自噬空泡和电子显微镜数据表明海藻糖的这些作用是由自噬介导的。用海藻糖处理3月龄PK-/-/Tau（VLW）小鼠4个月，可维持tau病理学和星形胶质细胞增生的改善，但未能逆转纹状体中的DA相关病理学。此外，14个月大的PK-/-/Tau（VLW）小鼠在其预期寿命的极限时用海藻糖治疗3周，改善了这些动物的运动行为和焦虑，并降低了它们的磷酸化tau水平和鼠β-淀粉样蛋白斑块的数量。由于海藻糖在高浓度下无毒性作用，因此本研究为海藻糖在人tau蛋白病中作用的临床研究开辟了道路。(C)2010年爱思唯尔公司All rights reserved.
Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms.We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK-/-/Tau(VLW)). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine beta-amyloid in the hippocampus.Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK-/-/Tau(VLW) phenotype. The treatment with trehalose of 3-month-old PK-/-/Tau(VLW) mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK-/-/Tau(VLW) and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK-/-/Tau(VLW) mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK-/-/Tau(VLW) mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine beta-amyloid plaques.Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies. (C) 2010 Elsevier Inc. All rights reserved.