Tau and Alzheimer's disease: Past, present and future.
Tau and Alzheimer's disease: Past, present and future.
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Tau 蛋白和阿尔茨海默病：过去、现在和未来。
DOI：
10.1002/cm.21822
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Iqbal,Khalid
中科院分区：
文献类型：
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作者：
Iqbal,Khalid
我和tau的旅程始于1974年，当时我第一次从阿尔茨海默病(AD)的尸检脑中分离出成对螺旋细丝(PHF)的神经原纤维缠结，并发现它们是由十二烷基硫酸钠-聚丙烯酰胺凝胶上的~50-70 kDa蛋白质组成的。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脑中神经原纤维缠结/PHF中的tau被异常过度磷酸化，并且与促进微管组装的正常tau不同，AD过度磷酸化tau抑制了微管组装。这些AD中tau病理学的发现开启了tau的一个新的主要研究领域，以及这一中老年痴呆的主要原因的分子病理学研究。Tau病理肯定是由蛋白质的聚集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家族的标志性病变，称为tauopathies。目前，tau病理学是治疗AD及相关tau病的主要药物靶点。处于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疗法，或者联合使用针对Aβ和/或神经退行性变的药物，以实现对AD和相关疾病的最有效治疗。
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.