RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.
RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.nbd.2014.05.029
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发表时间：
2014-09
影响因子：
6.1
通讯作者：
Lakshmana MK
中科院分区：
文献类型：
--
作者：
Wang R;Palavicini JP;Wang H;Maiti P;Bianchi E;Xu S;Lloyd BN;Dawson-Scully K;Kang DE;Lakshmana MK
我们先前已证明，在阿尔茨海默病（AD）小鼠模型中，RanBP9过表达会增加Aβ生成和淀粉样斑块负荷，进而导致几种突触蛋白水平大幅降低以及学习和记忆能力缺陷。在本研究中，我们发现与野生型（WT）神经元相比，来自RanBP9转基因小鼠（RanBP9 - Tg）的原代皮质神经元中，亲棘蛋白免疫反应性斑点显著减少（52%，p<0.001），亲棘蛋白面积显著减少（62.5%，p<0.001）。在转染了EGFP - RanBP9的野生型皮质神经元中也证实了类似结果。在6个月大时，RanBP9单转基因、APΔE9双转基因和APΔE9/RanBP9三转基因小鼠皮质中的总棘突密度与野生型小鼠相似。然而，在海马体中，由于细棘突数量减少（33%，p<0.05）和蘑菇状棘突数量减少（22%，p<0.05），三转基因小鼠的棘突密度与野生型小鼠相比显著降低（27%，p<0.05）。这表明在APΔE9小鼠中RanBP9过表达会加速棘突丢失，并且海马体更易受损。在12个月大时，与野生型对照组相比，由于蘑菇状棘突和细棘突减少，RanBP9（22%，p<0.05）、APΔE9（19%，p<0.05）和APΔE9/RanBP9（33%，p<0.01）小鼠的皮质中总棘突密度显著降低。同样，在海马体中，由于细棘突和蘑菇状棘突减少，RanBP9（23%，p<0.05）、APΔE9（26%，p<0.05）和APΔE9/RanBP9（39%，p<0.01）小鼠的总棘突密度降低。最重要的是，在APΔE9小鼠中RanBP9过表达进一步加剧了皮质（14%，p<0.05）和海马体（16%，p<0.05）中棘突密度的降低。由于树突棘被认为是记忆的物理痕迹，RanBP9导致的棘突丢失为学习和记忆缺陷提供了物理基础。由于AD大脑中RanBP9蛋白水平升高，RanBP9可能在AD的棘突和突触丢失中起关键作用。
We previously demonstrated that RanBP9 overexpression increased Aβ generation and amyloid plaque burden, subsequently leading to robust reductions in the levels of several synaptic proteins as well as deficits in the learning and memory skills in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin-immunoreactive puncta (52%, p<0.001) and spinophilin area (62.5%, p<0.001) in the primary cortical neurons derived from RanBP9 transgenic mice (RanBP9-Tg) compared to wild-type (WT) neurons. Similar results were confirmed in WT cortical neurons transfected with EGFP-RanBP9. At 6-months of age, the total spine density in the cortex of RanBP9 single transgenic, APΔE9 double transgenic and APΔE9/RanBP9 triple transgenic mice were similar to WT mice. However, in the hippocampus the spine density was significantly reduced (27%, p<0.05) in the triple transgenic mice compared to WT mice due to reduced number of thin spines (33%, p<0.05) and mushroom spines (22%, p<0.05). This suggests that RanBP9 overexpression in the APΔE9 mice accelerates loss of spines and that hippocampus is more vulnerable. At 12-months of age, cortex showed significant reductions in total spine density in the RanBP9 (22%, p<0.05), APΔE9 (19%, p<0.05) and APΔE9/RanBP9 (33%, p<0.01) mice compared to WT controls due to reductions in mushroom and thin spines. Similarly, in the hippocampus the total spine density was reduced in the RanBP9 (23%, p<0.05), APΔE9 (26%, p<0.05) and APΔE9/RanBP9 (39%, p<0.01) mice due to reductions in thin and mushroom spines. Most importantly, RanBP9 overexpression in the APΔE9 mice further exacerbated the reductions in spine density in both the cortex (14%, p<0.05) and the hippocampus (16%, p<0.05). Because dendritic spines are considered physical traces of memory, loss of spines due to RanBP9 provided the physical basis for the learning and memory deficits. Since RanBP9 protein levels are increased in AD brains, RanBP9 might play a crucial role in the loss of spines and synapses in AD.
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影响因子：
6.1
作者：
Hongpaisan, Jarin;Xu, Changqing;Alkon, Daniel L.
通讯作者：
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影响因子：
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