Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy
Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy
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DOI：
10.1042/bst0380564
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发表时间：
2010-04-01
影响因子：
3.9
通讯作者：
Mudher, Amritpal
中科院分区：
文献类型：
--
作者：
Cowan, Catherine M.;Chee, Francis;Mudher, Amritpal
轴突微管对物质向突触的运输至关重要。微管受损和突触丧失已在AD（阿尔茨海默病）中得到证实，这被认为是在疾病早期阶段神经元死亡之前导致认知功能障碍的原因。过度磷酸化的tau蛋白（神经原纤维缠结的组成部分，阿尔茨海默病的病理标志之一）破坏神经元和突触功能的机制尚不清楚。有一种理论认为，过度磷酸化的tau不能有效地与微管结合，不再能够稳定微管，因此轴突运输不能再有效地进行。这会导致突触功能障碍。我们已经在果蝇的tau病模型中测试了这一理论，其中我们表达了人类tau （h-tau）。使用这个模型，我们测试了这一假设的所有方面，并证明轴突运输确实在h-tau过度磷酸化的情况下受到损害，这导致突触和行为缺陷。我们目前正在研究过度磷酸化的h-tau介导这种效应的机制，初步数据表明，这需要由tau微管假说预测的磷酸化tau介导的效应，以及新的效应。h-tau的这些有害作用发生在tau纤维缺失和神经元死亡之前。这一系列致病事件可能构成了异常tau破坏神经元和突触功能的机制，并在AD等tau病的早期阶段神经元死亡之前导致认知障碍。
Axonal microtubules are essential for transport of materials to the synapse. Compromised microtubules and synaptic loss have been demonstrated in AD (Alzheimer's disease), which is believed to contribute to cognitive dysfunction before neuronal death in the early stages of the disease. The mechanism by which hyperphosphorylated tau, the building block of neurofibrillary tangles, one of the pathological hallmarks of AD, disrupts neuronal and synaptic function is unclear. There is a theory that hyperphosphorylated tau does not bind effectively to microtubules and is no longer able to function in stabilizing them, thus axonal transport can no longer proceed efficiently. This leads to synaptic dysfunction. We have tested this theory in a Drosophila model of tauopathies in which we expressed human tau (h-tau). Using this model, we have tested all aspects of this hypothesis and have demonstrated that axonal transport does become compromised in the presence of hyperphosphorylated h-tau and this leads to synaptic and behavioural defects. We are currently investigating the mechanism by which hyperphosphorylated h-tau mediates this effect and are preliminary data indicate that this entails phospho-tau-mediated effects that are predicted by the tau-microtubule hypothesis, as well as novel effects. These deleterious effects of h-tau occur in the absence of tau filaments and before neuronal death This sequence of pathogenic events may constitute the mechanism by which abnormal tau disrupts neuronal and synaptic function and contributes to cognitive impairment before neuronal death in the early stages of tauopathies such as AD.