Independent APOE4 knock-in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines.
Independent APOE4 knock-in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines.
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DOI：
10.1111/jnc.15665
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发表时间：
2022-11
影响因子：
4.7
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中科院分区：
文献类型：
--
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载脂蛋白E是大脑中的一种免疫调节剂，是晚发性阿尔茨海默病（AD）的主要遗传危险因素。靶向替代APOE小鼠（APOE-TR）已成为研究APOE亚型对AD前和AD期间脑神经化学和活动影响的有用工具。我们使用一种新的APOE基因敲入小鼠（JAX-APOE）来比较不同模型中与APOE 4相关的表型。与APOE 4-TR小鼠相似，JAX-E4小鼠脑中的APOE蛋白水平比JAX-E3低27%（p<0.001）。我们分析了几种与APOE基因型相关的神经炎症分子。SerpinA 3在APOE 4-TR小鼠中比APOE 3-TR小鼠高得多，但在JAX-APOE小鼠中未观察到这种效应。与JAX-E3相比，JAX-E4脑中IL-3水平较高，但其他神经炎症标志物（IL 6，TNFα）不受APOE基因型的影响。在神经元结构方面，JAX-E4小鼠内嗅皮层中的基础树突棘密度比JAX-E3小鼠低39%（p<0.001），再次与APOE-TR小鼠相似。用布洛芬治疗一周显著增加JAX-E4小鼠的树突棘密度，这与我们之前在APOE-TR小鼠中的发现一致。在行为学上，APOE基因型对6月龄JAX-APOE小鼠的巴恩斯迷宫学习和记忆没有影响。总体而言，在JAX-APOE小鼠中进行的实验验证了APOE-TR小鼠的发现，确定了APOE 4基因型对较低APOE蛋白水平和简化神经元结构的特别强烈的影响。这些数据证明了可能促进APOE 4脑对AD病理变化的易感性的途径。我们比较了两种靶向替代APOE小鼠模型（APOE-TR和JAX-APOE小鼠）中与APOE 4相关的表型。在整个模型中，与APOE 3相比，APOE 4基因型导致APOE蛋白水平降低，基线炎症标志物改变，树突棘密度简化。一周的Iceland治疗恢复了APOE 4小鼠的树突棘。我们的结论是，APOE 4基因型的最强效应是降低APOE蛋白水平和简化神经元结构，这是促进大脑对AD易感性的途径
APOE is an immunomodulator in the brain and the major genetic risk factor for late onset Alzheimer’s disease (AD). Targeted replacement APOE mice (APOE-TR) have been a useful tool to study the effects of APOE isoforms on brain neurochemistry and activity prior to and during AD. We use a newly available APOE knock-in mice (JAX-APOE) to compare phenotypes associated with APOE4 across models. Similar to APOE4-TR mice, JAX-E4 mouse brains showed 27% lower levels of APOE protein compared to JAX-E3 (p<0.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in APOE4-TR mice to APOE3-TR mice, but this effect was not seen in JAX-APOE mice. There were higher levels of IL-3 in JAX-E4 brains compared to JAX-E3, but other neuroinflammatory markers (IL6, TNFα) were not affected by APOE genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX-E4 mice compared to JAX-E3 mice (p<0.001), again similar to APOE-TR mice. One-week treatment with ibuprofen significantly increased dendritic spine density in the JAX-E4 mice, consistent with our previous finding in APOE-TR mice. Behaviorally, there was not an effect of APOE genotype on Barnes Maze learning and memory in six-month old JAX-APOE mice. Overall, the experiments performed in JAX-APOE mice validated findings from APOE-TR mice, identifying particularly strong effects of APOE4 genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of APOE4 brains to AD pathological changes. We compared phenotypes associated with APOE4 in two targeted replacement APOE mouse model, APOE-TR and JAX-APOE mice. APOE4 genotype results in reduced APOE protein levels, altered inflammatory markers at baseline, and simplified dendritic spine density compared to APOE3 across model. One week Ibuprofen treatment restored dendritic spine in APOE4 mice. We conclude that the strongest effects of APOE4 genotype are decreased APOE protein levels and simplified neuron structure, pathways that promote brain susceptibility to AD
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影响因子：
105.7
作者：
Etminan, M;Gill, S;Samii, A
通讯作者：
Samii, A
影响因子：
5.3
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Boehm-Cagan, Anat;Michaelson, Daniel M.
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Bour, Alexandra;Grootendorst, Jeannette;Mathis, Chantal
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影响因子：
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影响因子：
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