Are tau aggregates toxic or protective in tauopathies?
Are tau aggregates toxic or protective in tauopathies?
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DOI：
10.3389/fneur.2013.00114
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发表时间：
2013
影响因子：
3.4
通讯作者：
Mudher A
中科院分区：
文献类型：
--
作者：
Cowan CM;Mudher A
高度磷酸化的tau聚集成聚集形式，如细丝和神经原纤维缠结，是阿尔茨海默病和其他tau病的决定性病理标志之一。因此，治疗策略集中在抑制tau磷酸化或破坏聚集。然而，动物模型表明，tau介导的功能障碍和毒性不需要聚集，而是由可溶性超磷酸化的tau引起的。多年来，我们从果蝇的光头病模型中得到的发现强化了这一点。我们已经证明高度磷酸化的野生型人类tau在体内引起突触功能障碍、轴突运输中断和细胞骨架不稳定导致的行为缺陷。这些缺陷在没有神经元死亡或纤维/缠结形成的情况下是明显的。不出所料，GSK-3β的药理学和遗传抑制都能挽救这些tau表型。然而，GSK-3β抑制也意外地增加tau蛋白水平，并产生不溶性颗粒状tau低聚物。我们的研究结果进一步表明，并非所有的不溶性tau聚集物都是有毒的，同时也强调了tau毒性是由高度磷酸化的可溶性tau介导的这一日益增长的共识。一些tau聚集物，特别是tau低聚物，是无毒的，甚至可能在体内对tau毒性有保护作用。这对新兴的溶解tau聚集体的治疗策略具有重要意义，这些治疗策略可能无效甚至适得其反。鉴于此，确定关键的有毒tau物种并了解它如何介导功能障碍和变性，以便开发有效的疾病改善疗法是必要的。
Aggregation of highly phosphorylated tau into aggregated forms such as filaments and neurofibrillary tangles is one of the defining pathological hallmarks of Alzheimer’s disease and other tauopathies. Hence therapeutic strategies have focused on inhibition of tau phosphorylation or disruption of aggregation. However, animal models imply that tau-mediated dysfunction and toxicity do not require aggregation but instead are caused by soluble hyper-phosphorylated tau. Over the years, our findings from a Drosophila model of tauopathy have reinforced this. We have shown that highly phosphorylated wild-type human tau causes behavioral deficits resulting from synaptic dysfunction, axonal transport disruption, and cytoskeletal destabilization in vivo. These deficits are evident in the absence of neuronal death or filament/tangle formation. Unsurprisingly, both pharmacological and genetic inhibition of GSK-3β rescue these tau phenotypes. However, GSK-3β inhibition also unexpectedly increases tau protein levels, and produces insoluble granular tau oligomers. As well as underlining the growing consensus that tau toxicity is mediated by a highly phosphorylated soluble tau species, our findings further show that not all insoluble tau aggregates are toxic. Some tau aggregates, in particular tau oligomers, are non-toxic, and may even be protective against tau toxicity in vivo. This has serious implications for emerging therapeutic strategies to dissolve tau aggregates, which might be ineffective or even counter-productive. In light of this, it is imperative to identify the key toxic tau species and to understand how it mediates dysfunction and degeneration so that the effective disease-modifying therapies can be developed.
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影响因子：
4.7
作者：
Campbell, BCV;McLean, CA;Li, QX
通讯作者：
Li, QX
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
9.9
作者：
ARRIAGADA, PV;GROWDON, JH;HYMAN, BT
通讯作者：
HYMAN, BT
影响因子：
2.1
作者：
Avila, Jesus;Perez, Mar;Hernandez, Felix
通讯作者：
Hernandez, Felix
影响因子：
2.9
作者：
Berry, RW;Abraha, A;Binder, LI
通讯作者：
Binder, LI