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人们主要以从对脑组织尸检获得的证据为依据认为，tau蛋白的异常纤维性沉积（该蛋白在正常发挥功能时其作用是稳定微管）在阿尔茨海默氏症和tau-相关额颞痴呆症中引起细胞凋亡和神经退化。
现在，对过度表达一种人类tau基因的转基因小鼠中的这些神经纤维纠结所做的活体多光子成像研究，显示了一个大相径庭的情形。半胱天冬酶激发（细胞凋亡的一个已知标志）是所观察到的第一个异常，发生在纠结形成之前数小时至数天。有纠结的神经细胞不是遭受死亡，而是好像寿命还很长，同时半胱天冬酶活性降低。
因此真实情况可能是这样的：引起神经退化的是可溶性tau，而不是纤维性tau。就以破坏纠结为目标的药物在对抗神经退化中的价值而言，这项工作的意思在很大程度上取决于神经纤维纠结是一种保护性因子、与疾病无关、还是与慢速作用的神经毒性相关。
（本文来自生技网：www.biogo.net）
来源：
Nature 464, 1201-1204 (22 April 2010) | doi:10.1038/nature08890; Received 29 May 2009; Accepted 10 February 2010; Published online 31 March 2010
Caspase activation precedes and leads to tangles
摘要：
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death1, 2, severe cytological abnormalities3, and markers of caspase activation and apoptosis4, 5, 6, leading to the idea that tangles cause neurodegeneration in Alzheimer’s disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are ‘off pathway’ to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
