Human apolipoprotein C-I expression in mice impairs learning and memory functions
Human apolipoprotein C-I expression in mice impairs learning and memory functions
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DOI：
10.1194/jlr.m700518-jlr200
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发表时间：
2008-04-01
影响因子：
6.5
通讯作者：
Mulder, Monique
中科院分区：
文献类型：
--
作者：
Abildayeva, Karlygash;Berbee, Jimmy F. P.;Mulder, Monique
APOC I的H2等位基因导致载脂蛋白C-I （APOC -I）基因表达增加，与APOE4等位基因处于遗传不平衡状态，可能是阿尔茨海默病（AD）的主要危险因素。我们发现apoc - 1蛋白存在于人类对照和AD大脑海马区域的星形胶质细胞和内皮细胞中。有趣的是，apoc - 1与AD大脑斑块中的r -淀粉样蛋白（A β）共定位，体外实验显示apoc - 1存在时A β的聚集被延迟。此外，还发现apoc - 1可加重可溶性A β寡聚物诱导的神经元死亡。为了确定apoc - 1在认知功能中的潜在作用，我们使用了人类(h) apoc - 1（+/0）转基因小鼠，这些小鼠在其整个大脑中表达apoc - 1 mRNA，并在星形胶质细胞和内皮细胞中表达apoc - 1蛋白。从hAPOC1（+/0）小鼠在物体识别任务（P = 0.012）和Morris水迷宫任务（P = 0.010）中的表现来看，与野生型小鼠相比，hAPOC1（+/0）小鼠的海马依赖学习和记忆功能受损。apoc - 1可能通过抑制apoe依赖性脂质代谢而影响学习。然而，内源性apoE的脑组织mRNA和蛋白水平在转基因和野生型小鼠之间没有差异。综上所述，人类apoE - 1的表达会损害小鼠的认知功能，而不依赖apoE的表达，这支持了apoE - 1在AD发展过程中的潜在调节作用。
The H2 allele of APOC I, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hippocampal regions in both human control and AD brains. Interestingly, apoC-I colocalized with R-amyloid (A beta) in plaques in AD brains, and in vitro experiments revealed that aggregation of A beta was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble A beta oligomer-induced neuronal death. To establish a potential role for apoC-I in cognitive functions, we used human (h) APOC1(+/0) transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1(+/0) mice displayed impaired hippocampal-dependent learning and memory functions compared with their wild-type litter-mates, as judged from their performance in the object recognition task (P = 0.012) and in the Morris water maze task (P = 0.010). ApoC-I may affect learning as a result of its inhibitory properties toward apoE-dependent lipid metabolism. However, no differences in brain mRNA or protein levels of endogenous apoE were detected between transgenic and wild-type mice. In conclusion, human apoC-I expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoC-I during the development of AD.