Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer’s disease (AD). Previously, we studied the role of caspase-3–cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3–cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins—Kinesin 1 (KIF5) and Dynein—we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2–mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD.

线粒体是突触必不可少的高度专业化的细胞器，它们的损伤导致阿尔茨海默氏病（AD）的神经退行性变。以前，我们研究了caspase-3切割的tau在AD线粒体功能障碍中的作用。在神经元中，这种与AD相关的tau形式的存在诱导线粒体断裂，并伴随着线粒体裂变调节剂Opa1的表达降低。更重要的是，我们表明半胱天冬酶裂解的tau影响线粒体运输，减少了神经元过程中移动线粒体的数量，而不影响其速度。但是，涉及这些事件的分子机制尚不清楚。我们研究了运动蛋白（激肽1和动力蛋白）和线粒体蛋白衔接子（RhoT1 / T2，突触蛋白，和TRAK2）在半胱天冬酶切割的tau诱导的线粒体运输失败中发挥作用。我们在大鼠海马神经元和永生化皮层神经元中表达了绿色荧光蛋白（GFP），GFP全长和GPF-caspase-3切割的tau蛋白（CN 1.4），并分析了这些蛋白在线粒体转运中的表达和定位规。我们观察到表达半胱天冬酶切割的tau的海马神经元显示出体细胞中线粒体群体的大量积累。这些变化伴随着明显的线粒体生物能缺乏，包括去极化，氧化应激和ATP产量的显着降低。更关键的是 半胱天冬酶切割的tau显着降低了永生的和原代海马神经元中TRAK2的表达，而不会影响RhoT1 / T2和突触蛋白的水平。另外，当我们分析运动蛋白-动蛋白1（KIF5）和Dynein-的表达时，我们没有检测到它们的表达，定位以及与线粒体结合的变化。有趣的是，与表达全长tau蛋白的神经元细胞相比，截短tau蛋白的表达显着增加了TRAK2与线粒体的联系。总而言之，这些结果表明，胱天蛋白酶切割的tau可能通过增加TRAK2-线粒体结合和减少可用于这些细胞器运动的ATP产生而影响线粒体运输。