1USF Health Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL 33613 USA.
2Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, FL 33613 USA.
Commun Biol. 2019 Mar 22;2:112. doi: 10.1038/s42003-019-0359-9. eCollection 2019.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic . The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是最常见的痴呆症形式。虽然 Aβ 的积累对 AD 的病因学至关重要，但微管相关蛋白 tau（MAPT）和 F-肌动蛋白切割蛋白 cofilin 对于 Aβ 的有害影响都是必需的。然而，tau 和 cofilin 之间的分子联系尚不清楚。在这项研究中，我们发现 cofilin 在体外、细胞内和体内与 tau 竞争直接结合微管，从而抑制 tau 诱导的微管组装。mit 的遗传减少减轻了 Tau-P301S 小鼠中的 tau 病和突触缺陷以及 tau 转基因 中的运动缺陷。cofilin 的致病性作用是通过激活的 cofilin 选择性介导的，因为活性但不是非活性的 cofilin 选择性地与微管蛋白相互作用，破坏微管并促进 tau 病。因此，这些结果表明激活的 cofilin 在促进 tau 病的神经毒性信号转导中发挥着重要的中介作用。
