此前的诸多研究显示，变异Tau蛋白堆积导致的脑神经细胞变性是引发认知症的主要原因之一。而日本研究人员经动物实验发现，正常Tau蛋白随着动物年龄增长也会出现堆积。这一发现将对认知症病因带来一种新认识。

日本理化研究所近日发布的新闻公报介绍说，Tau蛋白大量存在于中枢神经细胞中，是构成脑神经网络的神经轴突发挥功能所必需的蛋白质。如果这种蛋白发生变异，在细胞内形成不溶的凝集，轴突运输就会受阻，导致神经细胞死亡。与这种蛋白相关的疾病统称“Tau蛋白病”，常见的有阿尔茨海默氏症等。

在本项研究中，来自理化研究所脑科学综合研究中心等机构的研究人员将人类Tau蛋白的基因植入实验鼠，使实验鼠脑内合成这种蛋白的量是其自身拥有量的约４至8倍。

研究人员发现，这些正常的可溶性蛋白随着实验鼠年龄的增长也会出现堆积，并且发生磷酸化，进而有可能使实验鼠脑内某特定区域发生神经变性，导致神经活动下降，从而引发“Tau蛋白病”。研究人员表示，下一步将研究正常Tau蛋白堆积的原因。

原文出处：

Neurobiology of Disease   DOI:10.1016/j.nbd.2011.02.002

Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice

Taiki Kambe, Yumiko Motoi, Ran Inoue, Nobuhiko Kojima, Norihiro Tada, Tetsuya Kimura, Naruhiko Sahara, Shunji Yamashita, Tatsuya Mizoroki, Akihiko Takashima, Kohei Shimada, Koichi Ishiguro, Hiroshi Mizuma, Hirotaka Onoe, Yoshikuni Mizuno and Nobutaka Hattor

Tauopathies differ in terms of the brain regions that are affected. In Alzheimer's disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (> 14 months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex–nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration.