Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice
Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice
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DOI：
10.1523/jneurosci.1937-12.2012
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发表时间：
2012-09-19
影响因子：
5.3
通讯作者：
Koldamova, Radosveta
中科院分区：
文献类型：
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作者：
Fitz, Nicholas F.;Cronican, Andrea A.;Koldamova, Radosveta
ATP结合盒转运体A1（ABCA1）转运体调节胆固醇外流，是高密度脂蛋白（HDL）形成的关键介质。在淀粉样前体蛋白（APP）转基因小鼠中，Abca1缺乏会使大脑中的淀粉样蛋白沉积增加，同时载脂蛋白E（ApoE）水平降低。APOE ε4等位基因是散发性阿尔茨海默病（AD）的主要遗传风险因素。在此，我们揭示了Abca1缺乏对表达人ApoE3或ApoE4的小鼠表型的影响。我们使用通过将APP/PS1ΔE9转基因小鼠与靶向替换人APOE3和APOE4的小鼠杂交产生的APP/E3和APP/E4小鼠，并研究了Abca1基因剂量对淀粉样蛋白沉积和认知的影响。两项行为测试的结果表明，缺少一个Abca1拷贝会显著加剧APP/E4/Abca1（+/-）小鼠的记忆缺陷，但不会加剧APP/E3/Abca1（+/-）小鼠的记忆缺陷。淀粉样斑块和不溶性β - 淀粉样蛋白（Aβ）的数据也显示，Abca1半合子状态仅在APP/E4/Abca1（+/-）小鼠中增加Aβ沉积，而不在APP/E3/Abca1（+/-）小鼠中增加。我们的体内微透析分析表明，Abca1缺乏会显著降低表达ApoE4的小鼠中Aβ的清除率，而Abca1对表达ApoE3的小鼠中Aβ清除率的影响不显著。此外，我们证明APP/E4/Abca1（+/-）小鼠的血浆HDL和Aβ42水平显著降低，并且血浆HDL与大脑中的淀粉样斑块呈负相关，这表明血浆脂蛋白可能参与Aβ的清除。总体而言，我们的结果证明功能性Abca1的存在显著影响表达人ApoE4的APP小鼠的表型，并进一步证实了基于ABCA1 - APOE调节轴的阿尔茨海默病治疗方法。
ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOE epsilon 4 allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect of Abca1 deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1 Delta E9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examined Abca1 gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy of Abca1 significantly exacerbates memory deficits in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. The data for amyloid plaques and insoluble amyloid-beta (A beta) also show that Abca1 hemizygosity increases A beta deposition only in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases A beta clearance in ApoE4-expressing mice, while the effect of Abca1 on A beta clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and A beta 42 levels in APP/E4/Abca1(-/+) mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in A beta clearance. Overall, our results prove that the presence of functional Abca1 significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1-APOE regulatory axis.