Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice.
Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice.
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DOI：
10.1186/1750-1326-6-39
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发表时间：
2011-06-06
影响因子：
15.1
通讯作者：
Kayed R
中科院分区：
文献类型：
--
作者：
Lasagna-Reeves CA;Castillo-Carranza DL;Sengupta U;Clos AL;Jackson GR;Kayed R
在阿尔茨海默病（AD）患者的脑中，tau的神经元缠结与疾病进展之间的相关性仍然是一个有争议的领域。生物化学、基于细胞的和转基因小鼠研究的创新数据表明，tau寡聚体（tau的前丝形式）可能是毒性最大和病理学上最显著的tau聚集体。在这里，我们报告，重组全长人tau蛋白的寡聚体在皮质下立体定位注射到小鼠体内后具有神经毒性。Tau寡聚体损害记忆巩固，而tau纤维和单体没有。此外，tau寡聚体通过降低突触囊泡相关蛋白synaptophysin和septin-11的水平诱导突触功能障碍。Tau寡聚体通过降低NADH-泛醌氧化还原酶（电子传递链复合物I）的水平和活化与凋亡线粒体途径相关的半胱天冬酶-9而产生线粒体功能障碍。这项研究将tau寡聚体鉴定为体内急性毒性tau种类，并表明tau寡聚体通过影响线粒体和突触功能诱导神经变性，这两者都是AD和其他tau蛋白病的早期标志。这些结果通过靶向tau寡聚体为tau蛋白病的神经保护干预策略开辟了新途径。
The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway. This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.
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DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
4.8
作者：
Davey, GP;Peuchen, S;Clark, JB
通讯作者：
Clark, JB
影响因子：
16.6
作者：
Caughey B;Baron GS;Chesebro B;Jeffrey M
通讯作者：
Jeffrey M
影响因子：
4.8
作者：
Diaz-Hernandez, Miguel;Gomez-Ramos, Alberto;Avila, Jesus
通讯作者：
Avila, Jesus