Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies.

Tau蛋白病是一种以tau蛋白病理性积累为特征的神经退行性疾病。Tau 在 tau 病患者的大脑中被过度磷酸化，并且这种磷酸化被认为在疾病发展中起作用。然而，目前尚不清楚不同 tau 蛋白病之间的磷酸化是否不同。在这里，我们研究了几种 tau 蛋白病中 tau 蛋白的磷酸化状态，包括皮质基底节变性、皮克病、进行性核上性麻痹 (PSP)、嗜银粒性痴呆 (AGD) 和阿尔茨海默病 (AD)。使用 Phos-tag SDS-PAGE 分析 tau 磷酸化谱揭示了不同 tau 病变中 tau 的不同磷酸化，而在同一 tau 病变中发现了相似的磷酸化模式。对于 PSP，我们发现了 2 种不同的磷酸化模式，表明 PSP 可能由 2 种不同的相关疾病组成。用抗磷酸化特异性抗体进行的免疫印迹显示，在患有不同 tau蛋白病的患者的颞叶中存在不同的位点特异性磷酸化。AD 大脑显示 Ser202、Thr231 和 Ser235 的磷酸化增加，Pick 病大脑显示磷酸化 Ser202 增加，而 AGD 大脑显示磷酸化 Ser396 增加。这在 AD 和 AGD 中，磷酸-Thr231 和 Pro232 (cis ptau) 之间肽键的顺式构象增加。这些结果表明，虽然 tau 在 tau 病变中的磷酸化程度不同，但在 AGD 和 AD 患者中可能会发生类似的病理机制。目前的数据提供了有关 tau 病理学和 tau 病变诊断的有用信息。