Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease
Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease
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DOI：
10.1042/bst0380545
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发表时间：
2010-04-01
影响因子：
3.9
通讯作者：
O'Connor, Vincent
中科院分区：
文献类型：
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作者：
Asuni, Ayodeji A.;Perry, V. Hugh;O'Connor, Vincent
微管相关蛋白tau的过度磷酸化是AD（阿尔茨海默病）中的重要决定因素，其与轴突运输中断相关并可能导致突触功能障碍。虽然研究较少，但在朊病毒疾病中已观察到过度磷酸化。我们研究了过度磷酸化tau蛋白在感染ME 7朊病毒的小鼠海马中的表达。在ME 7感染的动物中，CA 1突触的选择性丧失，在疾病的13周时首次可辨别。有一个潜在的功能障碍轴突运输有助于这种突触病。因此，研究AD中功能失调的过度磷酸化tau蛋白可以阐明它们在朊病毒疾病中是否以及如何重要。我们观察到在从ME 7-和NBH-（正常脑匀浆）处理的动物中提取的洗涤剂可溶性和洗涤剂不溶性级分中磷酸化tau（使用MC 1、PHF-1和CP 13抗体）的水平在疾病中没有差异。相比之下，我们在ME 7感染的海马切片中使用免疫组织化学观察到几个表位的磷酸化tau染色增加。尽管这些变化不是AD组织中所见的量级，但在ME 7处理的动物的CA 1和CA 3中观察到几种磷酸化tau种类的明显差异（pSer（199-202）>pser（214）>PHF-1抗体）。从时间上看，这些变化仅限于20周时的动物，并且没有任何疾病相关的染色与保持CA 1突触的轴突或树突相关。这些发现表明，tau蛋白在所检查的表位处的磷酸化并不支持早期突触功能障碍。这些数据表明，当早期功能障碍进展为明显的神经元损失时，这里记录的和其他人观察到的tau蛋白磷酸化的变化与终末期朊病毒病理学有关。
Hyperphosphorylation of the microtubule-associated protein tau is a significant determinant in AD (Alzheimer's disease), where it is associated with disrupted axonal transport and probably causes synaptic dysfunction. Although less well studied, hyperphosphorylation has been observed in prion disease. We have investigated the expression of hyperphosphorylated tau in the hippocampus of mice infected with the ME7 prion agent. In ME7-infected animals, there is a selective loss of CA1 synapse, first discernable at 13 weeks of disease. There is a potential that dysfunctional axonal transport contributes to this synaptopathy. Thus investigating hyperphosphorylated tau that is dysfunctional in AD could illuminate whether and how they are significant in prion disease. We observed no differences in the levels of phosphorylated tau (using MC1, PHF-1 and CP13 antibodies) in detergent-soluble and detergent-insoluble fractions extracted from ME7- and NBH- (normal brain homogenate) treated animals across disease. In contrast, we observed an increase in phospho-tau staining for several epitopes using immunohistochemistry in ME7-infected hippocampal sections. Although the changes were not of the magnitude seen in AD tissue, clear differences for several phospho-tau species were seen in the CA1 and CA3 of ME7-treated animals (pSer(199-202)>pser(214)>PHF-1 antibody). Temporally, these changes were restricted to animals at 20 weeks and none of the disease-related staining was associated with the axons or dendrites that hold CA1 synapses. These findings suggest that phosphorylation of tau at the epitopes examined does not underpin the early synaptic dysfunction. These data suggest that the changes in tau phosphorylation recorded here and observed by others relate to end-stage prion pathology when early dysfunctions have progressed to overt neuronal loss.