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低密度脂蛋白受体基因敲除小鼠表现出空间认知受损，海马体易发生细胞凋亡且突触存在缺陷。

LDL receptor knock-out mice show impaired spatial cognition with hippocampal vulnerability to apoptosis and deficits in synapses.

作者信息

Wang Shao-hua, Huang Yan, Yuan Yang, Xia Wen-qing, Wang Pin, Huang Rong

机构信息

Department of Endocrinology, ZhongDa Hospital of Southeast University, No,87 DingJiaQiao Road, Nanjing 210009, PR China.

出版信息

Lipids Health Dis. 2014 Nov 20;13:175. doi: 10.1186/1476-511X-13-175.

DOI:10.1186/1476-511X-13-175
PMID:25413784
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4258039/
Abstract

BACKGROUND

Evidence from clinical studies support the fact that abnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction. The low-density lipoprotein receptor (LDLR) is well-known for its role in regulating cholesterol metabolism. Whether LDLR involved in this impaired cognition and the potential mechanisms that underlie this impairment are unknown.

METHODS

Twelve-month-old Ldlr-/- mice (n = 10) and wild-type littermates C57BL/6 J (n = 14) were subjected to the Morris water maze test. At 1 week after completion of the behavioural testing, all of the animals were sacrificed for analysis of synaptic and apoptotic markers.

RESULTS

The plasma cholesterol concentration of Ldlr-/- mice was increased moderately when compared with C57BL/6 J mice (P < 0.05). Behavioural testing revealed that Ldlr-/- mice displayed impaired spatial memory, and moreover, the expression levels of synaptophysin and the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and dentate gyrus were decreased (all P < 0.05). Ultrastructural changes in the dentate gyrus were observed using transmission electron microscopy. Furthermore, apoptosis in the hippocampus of Ldlr-/- mice was revealed based on elevation, at both the mRNA and protein levels, of the ratio of Bax/Bcl-2 expression (all P < 0.05)and an increase in activated-caspase3 protein level (P < 0.05).

CONCLUSION

LDLR deficiency contributes to impaired spatial cognition. This most likely occurs via negative effects that promote apoptosis and synaptic deficits in the hippocampus.

摘要

背景

临床研究证据支持大脑中胆固醇代谢异常会导致进行性认知功能障碍这一事实。低密度脂蛋白受体（LDLR）因其在调节胆固醇代谢中的作用而广为人知。LDLR是否参与这种认知障碍以及这种障碍背后的潜在机制尚不清楚。

方法

对12月龄的Ldlr-/-小鼠（n = 10）和野生型同窝小鼠C57BL/6 J（n = 14）进行莫里斯水迷宫试验。行为测试完成1周后，处死所有动物以分析突触和凋亡标志物。

结果

与C57BL/6 J小鼠相比，Ldlr-/-小鼠的血浆胆固醇浓度适度升高（P < 0.05）。行为测试显示，Ldlr-/-小鼠表现出空间记忆受损，此外，海马CA1区和齿状回中突触素的表达水平以及突触素免疫反应性突触前终扣的数量均降低（均P < 0.05）。使用透射电子显微镜观察齿状回的超微结构变化。此外，基于Bax/Bcl-2表达比值在mRNA和蛋白质水平的升高（均P < 0.05）以及活化的半胱天冬酶3蛋白水平的增加（P < 0.05），揭示了Ldlr-/-小鼠海马中的细胞凋亡。

结论

LDLR缺乏导致空间认知受损。这很可能是通过促进海马细胞凋亡和突触缺陷的负面影响而发生的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/3b90b0bbef49/12944_2014_1163_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/09db1e90d554/12944_2014_1163_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/a1e5e15ce784/12944_2014_1163_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/4a5bf3c33ff9/12944_2014_1163_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/b4c5a23736bf/12944_2014_1163_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/29489a620cd3/12944_2014_1163_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/3b90b0bbef49/12944_2014_1163_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/09db1e90d554/12944_2014_1163_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/a1e5e15ce784/12944_2014_1163_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/4a5bf3c33ff9/12944_2014_1163_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/b4c5a23736bf/12944_2014_1163_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/29489a620cd3/12944_2014_1163_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a9d/4258039/3b90b0bbef49/12944_2014_1163_Fig6_HTML.jpg

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