J. Neurosci.：动物模型新研究表明Tau抗体药物有助于治疗阿尔茨海默病

来自美国宾夕法尼亚大学医学院的研究人员在2012年阿尔茨海默病协会主办的国际会议上报道，一种被称作epithilone D(EpoD)的tau抗体药物能够有效地在动物模型中防治阿尔茨海默病的发展，改善神经元功能和认知，同时降低tau病理特征。

通过靶向tau，这种抗体药物旨在让微管保持稳定，从而有助于促进必需营养物质和信息在细胞之间进行传输。当tau不起作用时，微管破裂，而且tau堆积而形成纤维缠结。宾夕法尼亚大学佩雷尔曼医学院病理学与临床医学教授John Trojanowski博士说，“在动物模型中，这种药物通过矫正tau功能丧失从而让微管保持稳定和弥补因形成神经原纤维缠结(neurofibrillary tangle)而造成的tau丢失，这就表明该药物有效地攻击靶标tau，同时还提示着调控阿尔茨海默病和其他基于tau 的神经退化疾病中的tau功能将可能成为一种重要的治疗选择。除了靶向淀粉样蛋白的药物---它们可能在晚期阿尔茨海默病中不能发挥作用---之外，我们希望这种药物和其他tau抗体药物能够在阿尔茨海默病患者体内进行测试以便确定让发生功能障碍的tau蛋白破坏的微管稳定化是否可能能够改变患者的临床结果和病理结果。”

在此之前，研究人员已证实这种药物能够阻止动物模型中的进一步神经损伤和改善认知。相关研究结果发表在Journal of Neuroscience期刊上。

本文编译自Anti-tau drug improves cognition, decreases tau tangles in Alzheimer's disease models

doi: 10.1523/​JNEUROSCI.3059-10.2010
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Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy

Kurt R. Brunden1,*, Bin Zhang1,*, Jenna Carroll1, Yuemang Yao1, Justin S. Potuzak2, Anne-Marie L. Hogan2, Michiyo Iba1, Michael J. James1, Sharon X. Xie3,4, Carlo Ballatore1,2, Amos B. Smith III2, Virginia M.-Y. Lee1, and John Q. Trojanowski

Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood–brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.