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Curr Biol:颠覆教条!《Cell》子刊:抗阿尔兹海默症药物或许会加速病情发展!

2018-07-02 Michael,Zoe 转化医学网

阿尔兹海默症,又叫老年痴呆,一直困扰世界范围内数以千计的患者,而Tau蛋白对于脑细胞微管的病理生理学作用一直被视为阿尔兹海默症的主要发病机制。医学研究领域一直认为Tau蛋白对于脑细胞微管具有稳定作用,而Peter W. Baas领导的研究团队发现Tau并不具备这种作用,相反,其还有具有不稳定的结构域。这意味着市面上很多治疗阿尔兹海默症的药物或许会加重病情的发展。

阿尔兹海默症,又叫老年痴呆,一直困扰世界范围内数以千计的患者,而Tau蛋白对于脑细胞微管的病理生理学作用一直被视为阿尔兹海默症的主要发病机制。医学研究领域一直认为Tau蛋白对于脑细胞微管具有稳定作用,而Peter W. Baas领导的研究团队发现Tau并不具备这种作用,相反,其还有具有不稳定的结构域。这意味着市面上很多治疗阿尔兹海默症的药物或许会加重病情的发展。

老年痴呆教条级研究:Tau对微管的稳定

目前流行的理论认为,患有神经退行性疾病的患者正在失去不稳定的微管。而该团队最新的研究表明,随着tau的消耗,患者实际上正在失去微管的动态区域,因此,通过使用微管稳定药物治疗神经退行性疾病,可能会使患者病情变得更加糟糕。

Tau是阿尔茨海默病的标志性蛋白质之一。在患病大脑中,tau从微管脱离并形成神经原纤维缠结,阻断营养成分向神经元的转运并最终杀死神经元。

改变微管稳定性的药物目前被认为是治疗阿尔茨海默氏病的潜在疗法,因为它几乎得到了科学界的普遍接受-Tau蛋白的具有稳定大脑的神经元,特别是轴突中的微管的作用。尽管存在这样普遍信念,但一个研究小组在20年前报道说,tau可能并不会影响微管的稳定性。研究人员决定通过消耗大鼠神经元中的tau并比较数天后轴突中的微管水平来深入研究这个问题。

颠倒教条:Tau允许微管生长并保持其动态变化。

来自Drexel大学医学院的科学家表示,他们最新的研究颠覆了医学界的科学教条-Tau蛋白质可稳定脑细胞内的微管。该团队的研究成果发表于近日的《Current Biology》中,他们认为 Tau在神经元中的实际作用是允许微管生长并保持其动态变化。

这项研究的主要作者Liang Oscar Qiang博士表示,微管的稳定区和动态区在大脑中保持活性至关重要,只有这样大脑才能保持正常的认知功能。

Qiang博士表示,大脑中存在如此之多的Tau蛋白是为了确保微管总保持动态变化,如果没有tau,那么大脑微管就会过于稳定。这项研究表明,目前临床试验中的微管稳定药物可能无法有效治疗阿尔茨海默氏病和其他基于tau的神经退行性疾病。他们发现微管在轴突中减少,不是由于它们变得不稳定,而是因为微管动态区域的优先损失。事实上,耗尽tau使得剩余的微管更稳定,这与之前的理论恰恰相反。研究人员说,这改变了我们对tau的基本理解。

究竟如何逆转阿尔兹海默症?

人们普遍认为tau可以稳定轴突中的微管,因此,疾病引起的tau微管损失导致其失去稳定性。轴突中的单个微管具有稳定的结构域和不稳定的结构域。该团队发现tau在不稳定域上更富集,这与tau提出的微管稳定剂的作用不一致。当tau从培养的大鼠神经元中耗尽时,轴突的不稳定微管显着下降,剩余的不稳定微管变得不那么不稳定,并且稳定的微管却有所增加。通常在稳定结构域上富集的MAP6在tau耗尽时在微管中获得更广的分布,为稳定微管的增加提供了解释。

当MAP6耗尽时,不稳定的微管团变得更加不稳定,这表明,与tau不同,MAP6是轴突微管的真正稳定剂。最后,研究人员得出这样的结论:tau不是轴突微管的稳定剂,而是在微管的不稳定区域富集以促进其组装,同时限制与真正稳定剂如MAP6的结合。这些结论与目前tau教条式的理论恰恰相反。

研究小组下一步将在成年啮齿动物大脑中重复类似的实验。 如果他们能够复制该研究结果,他们将通过新的治疗方法恢复微管失去的动态区域,寻求“恢复神经退行性大脑中丢失的东西”。

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    2018-07-04 维他命
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    2018-09-01 嗾笏

    长知识了

    0

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    2019-04-10 sunylz
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    2018-07-05 虈亣靌

    好好学习天天向上认真学习

    0

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