Abnormal protein accumulation and mislocalization is a general hallmark of Alzheimer disease. Recent data suggest nucleocytoplasmic transport may be compromised by tau in Alzheimer disease. In this context, we have examined the RNA polymerase II subunit RPB1, which is the catalytic subunit that plays a critical role in transcription. Using immunofluorescence staining in control and Alzheimer disease hippocampal tissue, we show that 2 phosphoisoforms of RPB1 mislocalize from the nucleus to the cytoplasm of neurons in Alzheimer disease. The number of neurons with this cytoplasmic mislocalization is correlated with the burden of pathologic tau (AT8-immunopositive neurons). In order to test whether there is a causal relationship between pathologic tau and cytoplasmic RPB1 accumulation, we used the rTg4510 mouse model, which expresses a regulatable pathologic human tau species harboring the P301L mutation. Using immunofluorescence staining on brain tissue from young (2.5-month-old) and aged (8.5- to 10-month-old) rTg4510 mice, we found a tau- and age-dependent increase in cytoplasmic mislocalization of Rpb1. In summary, this study provides evidence that tau induces mislocalization of RPB1 in Alzheimer disease, and since RPB1 is essential for transcription, this raises the possibility that RPB1 mislocalization could lead to fundamental alterations in neuronal health.

中文翻译：

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RNA聚合酶II亚基RPB1在阿尔茨海默病中的细胞质错误定位与病理性Tau有关

异常的蛋白质积累和错误定位是阿尔茨海默病的一般标志。最近的数据表明，在阿尔茨海默病中，tau 可能会影响核质转运。在这种情况下，我们检查了 RNA 聚合酶 II 亚基 RPB1，它是在转录中起关键作用的催化亚基。在对照和阿尔茨海默病海马组织中使用免疫荧光染色，我们发现 RPB1 的 2 种磷酸亚型在阿尔茨海默病中从细胞核错误定位到神经元的细胞质。具有这种细胞质错误定位的神经元数量与病理性 tau（AT8 免疫阳性神经元）的负担相关。为了测试病理性 tau 与细胞质 RPB1 积累之间是否存在因果关系，我们使用了 rTg4510 小鼠模型，它表达了一种具有 P301L 突变的可调节病理性人类 tau 物种。通过对年轻（2.5 个月大）和老年（8.5 至 10 个月大）rTg4510 小鼠的脑组织进行免疫荧光染色，我们发现 Rpb1 细胞质错误定位的 tau 和年龄依赖性增加。总之，这项研究提供了证据表明 tau 诱导 RPB1 在阿尔茨海默病中的错误定位，并且由于 RPB1 对转录至关重要，这增加了 RPB1 错误定位可能导致神经元健康发生根本性改变的可能性。