Truncated tau and Aβ cooperatively impair mitochondria in primary neurons.
Truncated tau and Aβ cooperatively impair mitochondria in primary neurons.
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DOI：
10.1016/j.neurobiolaging.2011.02.007
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发表时间：
2012-03
影响因子：
4.2
通讯作者：
Johnson GV
中科院分区：
文献类型：
--
作者：
Quintanilla RA;Dolan PJ;Jin YN;Johnson GV
线粒体功能障碍可能是阿尔茨海默病发病机制的一个重要因素，Aβ和病理形式的tau可能有助于这种损害。tau蛋白在Asp421处的裂解发生在阿尔茨海默病的早期，Asp421裂解的tau蛋白可能对神经元功能产生负面影响。以前我们表明，在神经元细胞模型中表达半胱天冬酶切割的tau蛋白导致线粒体损伤。为了扩展这些发现，我们在原代皮层神经元中表达全长tau或Asp421切割的tau（截短的tau），并在添加或不添加亚致死浓度的Aβ的情况下测量线粒体功能的不同方面。单独的截短tau蛋白的表达诱导神经元中显著的线粒体片段化。当截短的tau蛋白表达与亚致死浓度的Aβ结合时，观察到皮质神经元中稳定的线粒体群体和氧化应激水平增加。在原代神经元中，截短的tau蛋白表达也增强了Aβ诱导的线粒体电位损失。这些新的发现表明，Asp421切割的tau和Aβ协同损伤线粒体，这可能导致阿尔茨海默病的神经元功能障碍。
Mitochondrial dysfunction is likely a significant contributing factor to Alzheimer disease pathogenesis, and both Aβ and pathological forms of tau may contribute to this impairment. Cleavage of tau at Asp421 occurs early in Alzheimer disease, and Asp421-cleaved tau likely negatively impacts neuronal function. Previously we showed that expression of caspase-cleaved tau in a neuronal cell model resulted in mitochondrial impairment. To extend these findings we expressed either full-length tau or Asp421-cleaved tau (truncated tau) in primary cortical neurons and measured different aspects of mitochondrial function with or without the addition of sub-lethal concentrations of Aβ. The expression of truncated tau alone induced significant mitochondrial fragmentation in neurons. When truncated tau expression was combined with Aβ at sub-lethal concentrations, increases in the stationary mitochondrial population and the levels of oxidative stress in cortical neurons were observed. Truncated tau expression also enhanced Aβ-induced mitochondrial potential loss in primary neurons. These new findings show that Asp421-cleaved tau and Aβ cooperate to impair mitochondria, which likely contributes to the neuronal dysfunction in Alzheimer disease.
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