My journey with tau started when in 1974 for the first time I isolated neurofibrillary tangles of paired helical filaments (PHFs) from autopsied Alzheimer's disease (AD) brains and discovered that they were made up of a ~50–70 KDa protein on SDS-polyacrylamide gels. Subsequently my team discovered that this PHF protein and the microtubule-associated factor called tau were one and the same protein. However, we found that tau in neurofibrillary tangles/PHFs in AD brain was abnormally hyperphosphorylated, and unlike normal tau, which promoted the assembly of tubulin into microtubules, the AD-hyperphosphorylated tau inhibited microtubule assembly. These discoveries of tau pathology in AD opened a new and a major area of research on tau and on the molecular pathology of this major cause of dementia in middle- and old-age individuals. Tau pathology, which without fail is made up of the aggregated hyperphosphorylated state of the protein, is also the hallmark lesion of a family of around 20 related neurodegenerative diseases, called tauopathies. Currently, tau pathology is a major drug target for the treatment of AD and related tauopathies. Both active and passive tau immunization human clinical trials at various stages are underway. Initial results range from negative to partially promising. Future studies will reveal whether tau therapy alone or in combination with drugs targeting Aβ and/or neurodegeneration will be required to achieve the most effective treatment for AD and related disorders.

中文翻译：

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Tau 蛋白和阿尔茨海默病：过去、现在和未来

我的 tau 之旅始于 1974 年，我第一次从尸检的阿尔茨海默病 (AD) 大脑中分离出成对螺旋丝 (PHF) 的神经原纤维缠结，并发现它们是由 SDS-聚丙烯酰胺上约 50–70 KDa 的蛋白质组成凝胶。随后我的团队发现这种 PHF 蛋白和微管相关因子 tau 是同一种蛋白。然而，我们发现AD大脑中神经原纤维缠结/PHF中的tau蛋白异常过度磷酸化，与促进微管蛋白组装成微管的正常tau蛋白不同，AD过度磷酸化的tau蛋白抑制微管组装。AD 中 tau 蛋白病理学的这些发现为 tau 蛋白以及中老年痴呆症主要原因的分子病理学研究开辟了一个新的主要领域。Tau 病理学无疑是由聚集的蛋白质过度磷酸化状态组成的，也是大约 20 种相关神经退行性疾病（称为 tau 病）家族的标志性病变。目前，tau 病理学是治疗 AD 和相关 tau 病的主要药物靶点。不同阶段的主动和被动tau免疫人体临床试验正在进行中。初步结果从负面到部分有希望。未来的研究将揭示是否需要单独使用 tau 蛋白疗法或与针对 Aβ 和/或神经变性的药物联合使用，才能实现 AD 及相关疾病的最有效治疗。