Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline.
Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline.
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线粒体融合抑制Tau病理诱导的神经变性和认知能力下降。
DOI：
10.3233/jad-215175
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发表时间：
2021
影响因子：
4
通讯作者：
Wang, Xinglong
中科院分区：
文献类型：
--
作者：
Wang, Luwen;Liu, Mengyu;Gao, Ju;Smith, Amber M.;Fujioka, Hisashi;Liang, Jingjing;Perry, George;Wang, Xinglong
关键词：
线粒体分裂和融合的异常是已知对线粒体功能的各个方面至关重要的动态过程，已有反复报道在阿尔茨海默病(AD)中发生改变。神经原纤维缠结被认为是阿尔茨海默病的一个显著特征，通常被认为是这种毁灭性疾病中神经变性的可能原因。了解线粒体动力学在肌萎缩侧索硬化症中的病理作用。将目前广泛使用的自闭症P301S转基因小鼠(P301S小鼠)与Mfn2基因在神经元中特异表达的转基因TMFN小鼠杂交，获得双转基因P301S/TMFN小鼠。对11个月龄的非转基因(NTG)、TMFN、P301S和P301S/TMFN小鼠的脑组织进行了电子显微镜、共聚焦显微镜、免疫印迹、组织学染色和线粒体、tau病理以及tau病理诱导的神经变性和胶质细胞的免疫染色分析。认知功能采用Barnes迷宫评定。与年龄匹配的NTG小鼠相比，P301S小鼠表现出线粒体断裂和Mfn2持续减少。当P301S小鼠与TMFN小鼠(P301S/TMFN小鼠)杂交时，神经元丢失和线粒体碎裂明显减轻。在P301S/TMFN小鼠中，tau蛋白过度磷酸化、丝状聚集体和硫代黄素-S阳性缠结也明显减轻。此外，与P301S小鼠相比，P301S/TMFN小鼠表现出明显的神经炎症抑制和认知能力改善。这些体内研究结果表明，促进线粒体融合可以抑制毒性tau的积累和相关的神经变性，这可能会防止AD和相关tauopathy的进展。
Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. To understand the pathological role of mitochondrial dynamics in the context of tauopathy. The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-months old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.