Tau facilitates Aβ-induced loss of mitochondrial membrane potential independent of cytosolic calcium fluxes in mouse cortical neurons.
Tau facilitates Aβ-induced loss of mitochondrial membrane potential independent of cytosolic calcium fluxes in mouse cortical neurons.
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DOI：
10.1016/j.neulet.2015.04.021
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发表时间：
2015-06-15
影响因子：
2.5
通讯作者：
Johnson GV
中科院分区：
文献类型：
--
作者：
Pallo SP;Johnson GV
阿尔茨海默病（AD）的定义是存在两个病理学标志，即由异常加工的tau蛋白形成的神经元内神经元缠结（NFT）和主要由淀粉样β肽（Aβ）形成的细胞外淀粉样斑块。在AD中，这两种蛋白质可能协同作用以损害神经元功能，并且有证据表明它们会聚的关键靶点之一是线粒体。例如，在大鼠原代皮层神经元中病理形式的tau的过表达由于线粒体的钙（Ca 2+）缓冲能力的损害而加剧Aβ诱导的线粒体膜电位（Δ μ m）损失。然而，尚未研究tau生理水平在介导Aβ诱导的线粒体功能障碍中的作用。因此，在本研究中，我们使用野生型（WT）和tau基因敲除（tau−/−）小鼠的原代神经元来研究内源性tau是否促进Aβ诱导的Δ Ca 2+丢失和细胞溶质钙（Ca 2 +cyt）的改变。敲除tau蛋白可显著保护小鼠原代皮层神经元免受低浓度Aβ42引起的Δ Δ Km损失，这支持了我们先前的发现。然而，与WT小鼠原代皮质神经元中观察到的结果相比，tau缺失导致Aβ处理后Ca 2 +cyt显著增加。这种意想不到的结果可以解释的结果表明，tau−/−神经元显示某些表型异常与Ca 2 +cyt的改变。总体而言，数据表明tau蛋白促进Aβ诱导的线粒体功能障碍，并且这种作用不依赖于Aβ诱导的Ca 2+细胞的改变。1
Alzheimer’s disease (AD) is defined by presence of two pathological hallmarks, the intraneuronal neurofibrillary tangle (NFT) formed by abnormally processed tau, and the extracellular amyloid plaques formed primarily by the amyloid beta peptide (Aβ). In AD it is likely that these two proteins act in concert to impair neuronal function, and there is evidence to suggest that one of the key targets on which they converge is the mitochondria. For example, overexpression of a pathologic form of tau in rat primary cortical neurons exacerbates Aβ-induced mitochondrial membrane potential (ΔΨm) loss due to impairment of the calcium (Ca2+) buffering capability of mitochondria. However the role of physiological levels of tau in mediating Aβ-induced mitochondrial dysfunction was not examined. Therefore in this present study we used primary neurons from wild type (WT) and tau knockout (tau−/−) mice to investigate whether endogenous tau facilitates Aβ–induced ΔΨm loss and alterations in cytosolic calcium (Ca2+cyt). Knocking out tau significantly protected mouse primary cortical neurons from loss of ΔΨm caused by low concentrations of Aβ42, which supports our previous findings. However, the absence of tau resulted in significantly greater increases in Ca2+cyt in response to Aβ treatment when compared to those observed in WT mouse primary cortical neurons. This unexpected outcome may be explained by findings that suggest tau−/− neurons display certain phenotypic abnormalities associated with alterations in Ca2+cyt. Overall, data indicate that tau facilitates Aβ-induced mitochondrial dysfunction and this effect is independent of Aβ-induced alterations in Ca2+cyt.1
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影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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10.1016/j.bbrc.2012.08.062
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作者：
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通讯作者：
Johnson GV