Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain
Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain
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DOI：
10.1016/j.ajpath.2011.07.004
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发表时间：
2011-10-01
影响因子：
6
通讯作者：
Spires-Jones, Tara L.
中科院分区：
文献类型：
--
作者：
Kopeikina, Katherine J.;Carlson, George A.;Spires-Jones, Tara L.
神经元缠结（NFT），即异常纤维形式的微管相关蛋白tau的细胞内内含物，在阿尔茨海默病（AD）和其他tau蛋白病中积累，并被认为引起神经元功能障碍，但tau介导的毒性的机制尚不确定。细胞培养物中的Tau过表达损害细胞器的定位和运输。在这里，我们测试的假设，在完整的大脑中，线粒体分布的变化发生继发于病理变化的tau蛋白。阵列断层扫描，一种高分辨率的成像技术，被用来检查线粒体在可逆的转基因（rTg）4510，可调节的转基因，小鼠模型和AD脑组织。在rTg 4510脑中，特别是在含有Alz 50阳性tau聚集体的胞体和神经突中，线粒体分布随着年龄的增长而逐渐被破坏。用强力霉素抑制可溶性tau蛋白表达导致线粒体分布完全恢复，尽管聚集的tau蛋白继续存在。对线粒体分布的影响发生在没有伴随的神经元线粒体大小的改变，通过阵列断层扫描和电子显微镜评估。在人AD组织中的Alz 50+神经元中也观察到类似的线粒体定位改变，证实了tau与在该动物模型中观察到的线粒体运输的相关性。由于异常恢复正常，如果可溶性tau蛋白在rTg 4510小鼠中被抑制，即使在纤维状tau蛋白夹杂物的持续存在下，我们认为可溶性tau蛋白在线粒体异常中起着重要作用，这可能导致AD中的神经元功能障碍。(Am J Pathol 2011，179：2071-2082; DOI：10.1016/j.ajpath.2011.07.004）
Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of naicrotubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50+ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD. (Am J Pathol 2011, 179: 2071-2082; DOI: 10.1016/j.ajpath.2011.07.004)