Centre for Biological Sciences, University of Southampton , Southampton , UK.
Front Neurol. 2013 Aug 13;4:114. doi: 10.3389/fneur.2013.00114. eCollection 2013.
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.
高度磷酸化的 tau 聚集形成纤维和神经原纤维缠结是阿尔茨海默病和其他 tau 病的定义性病理特征之一。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，而是由可溶性高磷酸化 tau 引起的。多年来，我们在 tau 病的果蝇模型中的发现加强了这一点。我们已经表明，高度磷酸化的野生型人类 tau 会导致突触功能障碍、轴突运输中断和细胞骨架不稳定，从而导致行为缺陷。这些缺陷在没有神经元死亡或纤维/缠结形成的情况下也是明显的。毫不奇怪，GSK-3β 的药理学和遗传学抑制都可以挽救这些 tau 表型。然而，GSK-3β 的抑制也出乎意料地增加了 tau 蛋白水平，并产生了不溶性颗粒状 tau 寡聚物。除了强调 tau 毒性是由高度磷酸化的可溶性 tau 物种介导的共识不断增加之外，我们的发现还进一步表明，并非所有不溶性 tau 聚集物都是有毒的。一些 tau 聚集物，特别是 tau 寡聚物，是无毒的，甚至可能在体内对 tau 毒性具有保护作用。这对溶解 tau 聚集物的新兴治疗策略产生了严重影响，这些策略可能无效甚至适得其反。有鉴于此，确定关键的毒性 tau 物种并了解其如何介导功能障碍和退化至关重要，以便开发有效的疾病修饰治疗方法。
