Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
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DOI：
10.1172/jci200420640
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发表时间：
2004-07-01
影响因子：
15.9
通讯作者：
Cotman, CW
中科院分区：
文献类型：
--
作者：
Rissman, RA;Poon, WW;Cotman, CW
神经原纤维缠结 (NFT) 由细胞骨架蛋白 tau 的异常聚集体组成。 NFT 与β淀粉样蛋白（Abeta）斑块以及神经元和突触损失一起构成了阿尔茨海默病（AD）的主要病理标志。最近的证据还表明，半胱天冬酶在 AD 进展早期被激活，可能在神经元丢失和 NFT 病理学中发挥作用。在这里，我们证明 tau 在 D421 (DeltaTau) 处被刽子手半胱天冬酶切割。 caspase 裂解后，DeltaTau 促进成核依赖性细丝形成，并容易采用早期病理 tau 标记物 MC1 识别的构象变化。 DeltaTau 可以被糖原合成酶激酶 3beta 磷酸化，随后被 NFT 抗体 PHF-1 识别。在转基因小鼠和 AD 大脑中，DeltaTau 与 NFT 的早期和晚期标记物相关，并与认知能力下降相关。此外，DeltaTau 与 Abeta(1-42) 共定位，并在体外由 Abeta(1-42) 诱导。总的来说，我们的数据表明，Abeta 积累会触发 caspase 激活，导致 tau 的 caspase 裂解，并且这是 AD 缠结病理学进化中可能先于过度磷酸化的早期事件。这些结果表明，旨在抑制 tau 半胱天冬酶裂解的治疗方法可能不仅有助于预防 NFT 形成，而且有助于减缓认知能力下降。
Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid beta (Abeta) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (DeltaTau) by executioner caspases. Following caspase-cleavage, DeltaTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. DeltaTau can be phosphorylated by glycogen synthase kinase-3beta and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, DeltaTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, DeltaTau colocalizes with Abeta(1-42) and is induced by Abeta(1-42) in vitro. Collectively, our data imply that Abeta accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.