The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.
The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.
复制标题
DOI：
10.1523/jneurosci.4922-11.2012
复制
发表时间：
2012-03-14
期刊：
影响因子：
--
通讯作者：
Brunden KR
中科院分区：
文献类型：
--
作者：
Zhang B;Carroll J;Trojanowski JQ;Yao Y;Iba M;Potuzak JS;Hogan AM;Xie SX;Ballatore C;Smith AB 3rd;Lee VM;Brunden KR
神经退行性tau蛋白病，如阿尔茨海默病（AD），特征在于脑神经元内过度磷酸化的tau蛋白的不溶性沉积。已经提出增加的磷酸化和降低的溶解度降低微管（MT）的正常tau稳定性，从而导致神经元功能障碍。早期的研究已经提供了证据表明，用于治疗癌症的小分子MT稳定药物可能在治疗tau蛋白病中具有效用。然而，尚未确定用小分子MT稳定化合物治疗是否将在具有预先存在的tau病理的Tg模型中提供益处，如在具有临床症状的人类患者中所见。因此，我们在这里描述了一项干预性研究的脑渗透MT稳定剂，埃博霉素D（EpoD），在老年PS19小鼠与现有的tau病理和相关的行为缺陷。EpoD治疗减少了老年PS19小鼠的轴突营养不良并增加了轴突MT密度，从而改善了快速轴突运输和认知能力。此外，EpoD处理的PS19小鼠前脑tau病理学较少，海马神经元完整性增加，没有剂量限制性副作用。这些数据表明，脑渗透MT稳定药物有望用于治疗AD和相关的tau蛋白病，并且EpoD可能是临床测试的候选药物。
Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.