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首页> 外文期刊>BMC Neuroscience >Hirano bodies differentially modulate cell death induced by tau and the amyloid precursor protein intracellular domain
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Hirano bodies differentially modulate cell death induced by tau and the amyloid precursor protein intracellular domain

机译：平野体差异调节tau和淀粉样前体蛋白胞内结构域诱导的细胞死亡

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Background Hirano bodies are actin-rich paracrystalline inclusions found in brains of patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and in normal aged individuals. Although studies of post-mortem brain tissue provide clues of etiology, the physiological function of Hirano bodies remains unknown. A cell culture model was utilized to study the interactions of mutant tau proteins, model Hirano bodies, and GSK3β in human astrocytoma cells. Results Most tau variants showed co-localization with model Hirano bodies. Cosedimentation assays revealed this interaction may be direct, as recombinant purified forms of tau are all capable of binding F-actin. Model Hirano bodies had no effect or enhanced cell death induced by tau in the absence of amyloid precursor protein intracellular domain (AICD). In the presence of AICD and tau, synergistic cell death was observed in most cases, and model Hirano bodies decreased this synergistic cell death, except for forms of tau that caused significant cell death in the presence of Hirano bodies only. A role for the kinase GSK3β is suggested by the finding that a dominant negative form of GSK3β reduces this synergistic cell death. A subset of Hirano bodies in brain tissue of both Alzheimer’s disease and normal aged individuals was found to contain tau, with some Hirano bodies in Alzheimer’s disease brains containing hyperphosphorylated tau. Conclusion The results demonstrate a complex interaction between tau and AICD involving activation of GSK3β in promoting cell death, and the ability of Hirano bodies to modulate this process.
机译：背景平野小体是在阿尔茨海默氏病（AD），额颞痴呆（FTD）和正常年龄的人的大脑中发现的富含肌动蛋白的顺晶体包裹体。尽管对尸体后脑组织的研究提供了病因学线索，但是平野尸体的生理功能仍然未知。细胞培养模型用于研究人类星形细胞瘤细胞中的突变tau蛋白，平野模型和GSK3β的相互作用。结果大多数tau变体与平野模型体共定位。沉淀分析表明，这种相互作用可能是直接的，因为重组重组形式的tau都能够结合F-肌动蛋白。在缺乏淀粉样前体蛋白胞内结构域（AICD）的情况下，模型平野体没有作用或增强的tau诱导的细胞死亡。在存在AICD和tau的情况下，大多数情况下观察到协同细胞死亡，并且模型性平野小体降低了这种协同性细胞死亡，除了tau的形式仅在存在平野小体的情况下才导致明显的细胞死亡。该发现表明，GSK3β的显性负性形式减少了这种协同细胞死亡，从而表明了GSK3β激酶的作用。发现阿尔茨海默氏病和正常老年人的脑组织中的平野小体中都含有tau，阿尔茨海默氏病脑中的一些平野体中也含有过度磷酸化的tau。结论结果表明tau与AICD之间复杂的相互作用涉及激活GSK3β促进细胞死亡，以及平野体调节该过程的能力。

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