Altered DNA repair; an early pathogenic pathway in Alzheimer's disease and obesity.
Altered DNA repair; an early pathogenic pathway in Alzheimer's disease and obesity.
复制标题
DNA 修复改变；
DOI：
10.1038/s41598-018-23644-4
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发表时间：
2018
影响因子：
4.6
通讯作者：
Xia,Fen
中科院分区：
文献类型：
--
作者：
Yu,Hao;Harrison,FionaEdith;Xia,Fen
未修复的 DNA 双链断裂 (DSB) 是致命的。本研究比较了喂食对照饮食或高脂饮食（60% 脂肪来自猪油）的 5-6 个月和 16-18 月龄野生型和 APP/PSEN1 小鼠海马中 DSB 的程度、神经元凋亡以及两种主要 DSB 修复途径（同源组合修复 (HR) 和非同源末端连接 (NHEJ)）的状态。我们对 DSB、RAD51 和 53BP1 的 γ-H2AX 核灶形成进行了免疫组织化学染色和定量，它们分别代表 HR 和 NHEJ 的功能状态。 γ-H2AX 和 caspase-3 染色的增加表明在所研究的两个年龄段的 APP/PSEN1 小鼠中 DSB 更大并且相关的神经元凋亡。 APP/PSEN1 中的 RAD51 阳性灶较少，表明这些小鼠的 HR 过程可能减弱，尽管 NHEJ（53BP1 染色）似乎没有变化。年轻野生型小鼠的高脂肪饮食导致了与 APP/PSEN1 小鼠中观察到的类似变化（γ-H2AX 和 caspase-3 染色，以及较少的 RAD51 阳性灶）。总体而言，这些数据表明，APP/PSEN1 和高脂肪饮食相关的 DSB 早期积累和神经元细胞死亡至少部分是由于 HR（主要 DSB 修复途径之一）的抑制所致。
Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5–6 month and 16–18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of γ-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased γ-H2AX and caspase-3 staining indicated greater DSBs and associated neuronal apoptosis in APP/PSEN1 mice at both ages studied. RAD51-positive foci were fewer in APP/PSEN1 indicating that HR processes may be diminished in these mice, although NHEJ (53BP1 staining) appeared unchanged. High fat diet in young wild-type mice led to similar changes to those observed in APP/PSEN1 mice (γ-H2AX and caspase-3 staining, and fewer RAD51-positive foci). Overall, these data suggest that APP/PSEN1- and high fat diet-associated early accumulation of DSBs and neuronal cell death, resulted at least in part, from inhibition of HR, one of the major DSB repair pathways.