Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2.
Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2.
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DOI：
10.1016/j.neuroscience.2010.10.027
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发表时间：
2010-12-29
期刊：
影响因子：
3.3
通讯作者：
Sullivan PM
中科院分区：
文献类型：
--
作者：
Klein RC;Mace BE;Moore SD;Sullivan PM
APOE 4等位基因的遗传是与晚发性阿尔茨海默病发展相关的公认遗传风险因素。载脂蛋白E（apolipoprotein，apo E）是中枢神经系统中主要的脂质转运蛋白，在突触连接的组装和维持中起着重要作用。我们以前的工作表明，与apoE 3 TR小鼠相比，7个月大的人apoE 4靶向置换（TR）小鼠在外侧杏仁核的主要神经元中显示出显著的突触缺陷，外侧杏仁核是记忆形成的关键区域，也是阿尔茨海默病中受影响的主要区域之一。在目前的研究中，我们确定了年龄和不同的APOE基因型如何影响杏仁核神经元的突触完整性，通过比较C57 BL 6，apoE基因敲除，和人类apoE 3，E4和E2/4 TR小鼠在1个月和7个月的电生理和形态学特性。在两个年龄段，apoE 4 TR小鼠的兴奋性突触活动和树突状乔木水平均低于其他同龄组，并在7个月时逐渐恶化。相比之下，apoE 3 TR小鼠在两个年龄的所有队列中表现出最高的突触活性和树突状乔木。C57 BL 6小鼠在1个月时表现出与apoE 3 TR小鼠几乎相同的突触活性;然而，该活性在7个月时降低。ApoE基因敲除小鼠在7个月时表现出与apoE 4 TR小鼠相似的突触活动特征。与先前关于APOE 2具有保护作用的报道一致，在两个年龄段的apoE 2/4 TR小鼠中，兴奋活性中的apoE 4依赖性缺陷显著减弱。这些发现表明，人类apoE 4的表达有助于杏仁核在发育早期的功能缺陷，并可能负责改变神经元回路，最终导致认知和情感障碍。
Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the assembly and maintenance of synaptic connections. Our previous work showed that 7 month old human apoE4 targeted replacement (TR) mice displayed significant synaptic deficits in the principal neurons of the lateral amygdala, a region that is critical for memory formation and also one of the primary regions affected in Alzheimer’s disease, compared to apoE3 TR mice. In the current study, we determined how age and varying APOE genotype affect synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in C57BL6, apoE knockout, and human apoE3, E4 and E2/4 TR mice at 1 month and 7 months. The apoE4 TR mice exhibited the lowest level of excitatory synaptic activity and dendritic arbor compared to other cohorts at both ages, and became progressively worse by 7 months. In contrast, the apoE3 TR mice exhibited the highest synaptic activity and dendritic arbor of all cohorts at both ages. C57BL6 mice displayed virtually identical synaptic activity to apoE3 TR mice at 1 month; however this activity decreased by 7 months. ApoE knockout mice exhibited a similar synaptic activity profile with apoE4 TR mice at 7 months. Consistent with previous reports that APOE2 confers protection, the apoE4-dependent deficits in excitatory activity were significantly attenuated in apoE2/4 TR mice at both ages. These findings demonstrate that expression of human apoE4 contributes to functional deficits in the amygdala very early in development and may be responsible for altering neuronal circuitry that eventually leads to cognitive and affective disorders later in life.
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影响因子：
56.9
作者：
MAHLEY, RW
通讯作者：
MAHLEY, RW
影响因子：
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作者：
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作者：
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作者：
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影响因子：
4.2
作者：
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