Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
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DOI：
10.1172/jci33622
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Holtzman, David M.
中科院分区：
文献类型：
--
作者：
Wahrle, Suzanne E.;Jiang, Hong;Holtzman, David M.
载脂蛋白E基因型是晚发性阿尔茨海默病（AD）的主要遗传危险因素。ABCA 1是主动转运蛋白ATP结合盒家族的成员，在CNS中脂化apoE。在几种AD小鼠模型中，Abca 1（-/-）小鼠具有与apoE相关的脂质降低和淀粉样蛋白沉积增加。我们假设，小鼠大脑中过表达ABCA 1会增加含apoE脂蛋白的脂化，减少淀粉样蛋白沉积。为了解决这些假设，我们创建了PrP-mAbca 1 Tg小鼠，在小鼠朊病毒启动子的控制下，在整个大脑中过表达小鼠Abca 1。我们将PrP-mAbca 1小鼠与PDAPP AD小鼠模型（一种过度表达突变型人淀粉样前体蛋白的转基因系）进行了交配。PDAPP/Abca 1 Tg小鼠的表型与PDAPP/Apoe（-/-）小鼠的表型非常相似：淀粉样β肽（A β）沉积显著减少，A β重新分布到海马齿状回门，几乎完全不存在硫磺素S阳性淀粉样斑块。对来自PrP-mAbca 1 Tg小鼠的CSF和PrP-mAbca 1 Tg原代星形胶质细胞条件培养基的分析表明，含apoE颗粒的脂化增加。这些数据支持以下结论：增加CNS中ABCA 1介导的apoE脂化可以减少淀粉样蛋白负荷，增加ABCA 1功能可能对AD具有治疗作用。
APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (A beta) deposition, a redistribution of A beta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.