Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism.
Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism.
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DOI：
10.18632/aging.101592
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发表时间：
2018-10-23
期刊：
影响因子：
--
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Yin J;Li S;Nielsen M;Carcione T;Liang WS;Shi J
阿尔茨海默病（AD）表现为局部脑代谢低下。Sirtuin 3（Sirt 3）定位于线粒体中并调节细胞代谢，但Sirt 3在AD相关的低代谢中的作用仍然是难以捉摸的。我们使用表达谱和加权基因共表达网络分析（WGCNA）来分析AD转基因小鼠模型（APPSwInd）的皮层神经元。基于WGCNA结果，我们测量了体内和体外模型中的NAD+水平、NAD+/ NADH比率、Sirt 3蛋白水平及其去乙酰化活性和ATP产生。为了研究Sirt 3在淀粉样蛋白β（Aβ）诱导的线粒体损伤中的作用，我们在海马细胞中敲低并过表达Sirt 3。WGCNA揭示Sirt 3是Aβ相关代谢减退的关键参与者。在APP小鼠中，与对照组相比，NAD+水平、NAD+/ NADH比率、Sirt 3蛋白水平和活性以及ATP产生均降低。结果，与野生型对照组相比，9个月大的APP小鼠的学习和记忆能力受损。在海马HT 22细胞模型中，Sirt 3的过表达增加了Aβ损伤的线粒体的去乙酰化活性，挽救了线粒体的功能，并挽救了ATP的产生。Sirt 3在Aβ诱导的脑代谢低下中起重要调节作用。该研究为AD的治疗提供了一个潜在的方向。
Alzheimer’s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.
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