线粒体 DNA 操作会影响 tau 寡聚化。
Mitochondrial DNA Manipulations Affect Tau Oligomerization.
机构信息
University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.
Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
出版信息
J Alzheimers Dis. 2020;77(1):149-163. doi: 10.3233/JAD-200286.
BACKGROUND
Mitochondrial dysfunction and tau aggregation occur in Alzheimer's disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau.
OBJECTIVE
To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations.
METHODS
Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects.
RESULTS
We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift.
CONCLUSION
We conclude a cell's mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.
背景
线粒体功能障碍和 tau 聚集发生在阿尔茨海默病（AD）中，使细胞或啮齿动物暴露于线粒体毒素会改变其 tau。
目的
为了进一步探讨线粒体如何影响 tau，我们通过对具有不同线粒体 DNA（mtDNA）操作的人神经元 SH-SY5Y 细胞测量 tau 寡聚物水平来进行研究。
方法
具体来说，我们分析了经历溴化乙锭诱导的急性 mtDNA 耗竭的细胞、慢性 mtDNA 耗竭的 ρ0 细胞以及含有 AD 受试者 mtDNA 的细胞质杂种（cybrid）细胞系。
结果
我们发现细胞色素氧化酶活性对急性 mtDNA 耗竭特别敏感，这表明 ρ0 细胞发生了代谢重编程，并且通过 AD 受试者线粒体转移产生的 cybrid 中的 mtDNA 含量相对减少。在每种情况下，tau 寡聚物水平均增加，急性耗竭和 AD cybrid 细胞也显示出单体到寡聚物的转变。
结论
我们得出结论，细胞的 mtDNA 会影响 tau 寡聚化。在三个 mtDNA 操作模型中重叠的 tau 变化确立了该现象的可重复性，并且在 AD cybrid 细胞中存在该现象支持了其与 AD 的相关性。
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