In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons
In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons
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DOI：
10.1523/jneurosci.3072-08.2008
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发表时间：
2008-01-23
影响因子：
5.3
通讯作者：
Hyman, Bradley T.
中科院分区：
文献类型：
--
作者：
Spires-Jones, Tara L.;De Calignon, Alix;Hyman, Bradley T.
阿尔茨海默病中神经元缠结（NFT）的积累与神经元损失和认知下降相关，但NFT与神经元死亡和细胞死亡的下游机制之间的确切关系仍不清楚。半胱天冬酶裂解产物在缠结中积累，这意味着缠结可能有助于凋亡性神经元死亡。为了验证这一假设，我们开发了使用多光子成像的方法来检测活体小鼠大脑中的神经病理学和半胱天冬酶激活。我们检查了rTg4510小鼠，这是一种可逆的tau蛋白病小鼠模型，可发生缠结和神经元丢失。只有一小部分成像的神经元是半胱天冬酶活性阳性的，但绝大多数具有活性半胱天冬酶的细胞含有NFT。我们接下来测试了半胱天冬酶激活导致急性凋亡性神经元死亡的假设。半胱天冬酶阳性细胞体在数小时的成像中没有退化，尽管存在激活的刽子手半胱天冬酶。抑制转基因，停止正在进行的死亡，没有抑制半胱天冬酶活性。最后，组织化学评估显示了半胱天冬酶切割的tau蛋白的证据，但没有TUNEL（末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记）阳性或凋亡细胞核。通过在活体脑中观察NFT和半胱天冬酶激活的新技术，我们证明了神经元中聚集的tau蛋白可以与半胱天冬酶激活相关，但是半胱天冬酶激活不足以在该模型中引起急性神经元死亡。
Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.