Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027
Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027
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DOI：
10.1523/jneurosci.0188-12.2012
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发表时间：
2012-05-23
影响因子：
5.3
通讯作者：
Albright, Charles F.
中科院分区：
文献类型：
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作者：
Barten, Donna M.;Fanara, Patrizia;Albright, Charles F.
Tau是一种微管（MT）稳定蛋白，在阿尔茨海默病（AD）和其他Tau病变中发生改变。假设tau蛋白的过度磷酸化、构象改变和多聚体形式导致MT稳定性的破坏;然而，缺乏体内直接证据。在这项研究中，在体内稳定的同位素质谱技术被用来测量营业额，或动态，MT在活体动物的大脑。我们在两种不同的tau转基因小鼠模型3xTg和rTg 4510中证明了MT动力学的年龄依赖性增加。MT hyperdynamicity依赖于tau蛋白的表达，因为用强力霉素减少转基因表达逆转了MT的变化。用埃博霉素BMS-241027治疗rTg 4510小鼠也将MT动力学恢复到基线水平。此外，用BMS-241027稳定MT对Morris水迷宫缺陷、tau病理学和神经变性具有有益作用。有趣的是，在仅部分逆转MT动力亢进的剂量下观察到BMS-241027的病理和功能益处。总之，这些数据表明，tau介导的MT稳定性丧失可能有助于疾病进展，并且非常低剂量的BMS-241027可用于治疗AD和其他tau蛋白病。
Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.