RanBP9 aggravates synaptic damage in the mouse brain and is inversely correlated to spinophilin levels in Alzheimer's brain synaptosomes.
RanBP9 aggravates synaptic damage in the mouse brain and is inversely correlated to spinophilin levels in Alzheimer's brain synaptosomes.
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DOI：
10.1038/cddis.2013.183
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发表时间：
2013-06-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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我们之前证明了RanBP9的过表达导致多种细胞系和原代神经元培养中a β生成增强，随后，我们证实了阿尔茨海默病（AD）小鼠模型中淀粉样斑块负荷增加。在本研究中，我们发现当RanBP9过表达时，嗜脊髓蛋白水平显著降低。在12个月大时，我们发现APΔE9/RanBP9小鼠皮层中的嗜脊髓蛋白水平与野生型（WT）对照相比降低了70% （P<0.001）。在海马中，APΔE9/RanBP9小鼠的嗜脊髓蛋白水平降低了45% （P<0.01）。APΔE9/RanBP9和APΔE9小鼠皮层嗜脊髓蛋白免疫反应性也分别降低22% （P<0.01）和12% （P<0.05）。在海马中，APΔE9/RanBP9和APΔE9小鼠分别减少27% （P<0.001）和14% （P<0.001）。然而，在APΔE9或APΔE9/RanBP9小鼠的小脑中，嗜脊髓蛋白水平没有改变。此外，与WT对照组相比，在基础条件下，APΔE9/RanBP9小鼠的突触体功能完整性降低了39% (P<0.001)， APΔE9小鼠的突触体功能完整性降低了23% （P<0.001）。在ATP和kcl刺激的条件下，我们观察到WT和APΔE9小鼠的线粒体活性较高，而APΔE9/RanBP9小鼠的线粒体活性较低。值得注意的是，我们证实了阿尔茨海默病大脑突触体中RanBP9-N60与嗜脊髓蛋白之间的反比关系。更重要的是，与WT对照组相比，APΔE9和APΔE9/RanBP9小鼠都表现出学习和记忆能力受损。这些数据表明，RanBP9可能在阿尔茨海默病中脊柱和突触的丧失中发挥关键作用。
We previously demonstrated that overexpression of RanBP9 led to enhanced Aβ generation in a variety of cell lines and primary neuronal cultures, and subsequently, we confirmed increased amyloid plaque burden in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin protein levels when RanBP9 is overexpressed. At 12 months of age, we found spinophilin levels reduced by 70% (P<0.001) in the cortex of APΔE9/RanBP9 mice compared with that in wild-type (WT) controls. In the hippocampus, the spinophilin levels were reduced by 45% (P<0.01) in the APΔE9/RanBP9 mice. Spinophilin immunoreactivity was also reduced by 22% (P<0.01) and 12% (P<0.05) in the cortex of APΔE9/RanBP9 and APΔE9 mice, respectively. In the hippocampus, the reductions were 27% (P<0.001) and 14% (P<0.001) in the APΔE9/RanBP9 and APΔE9 mice, respectively. However, in the cerebellum, spinophilin levels were not altered in either APΔE9 or APΔE9/RanBP9 mice. Additionally, synaptosomal functional integrity was reduced under basal conditions by 39% (P<0.001) in the APΔE9/RanBP9 mice and ∼23% (P<0.001) in the APΔE9 mice compared with that in WT controls. Under ATP- and KCl-stimulated conditions, we observed higher mitochondrial activity in the WT and APΔE9 mice, but lower in the APΔE9/RanBP9 mice. Significantly, we confirmed the inverse relationship between RanBP9-N60 and spinophilin in the synaptosomes of Alzheimer's brains. More importantly, both APΔE9 and APΔE9/RanBP9 mice showed impaired learning and memory skills compared to WT controls. These data suggest that RanBP9 might play a crucial role in the loss of spines and synapses in AD.
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DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
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影响因子：
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Lakshmana, Madepalli K.;Chung, John Y.;Kang, David E.
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DOI：
10.1073/pnas.0600948103
发表时间：
2006-03-28
影响因子：
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作者：
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通讯作者：
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影响因子：
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