Deletion of Abca7 Increases Cerebral Amyloid-β Accumulation in the J20 Mouse Model of Alzheimer's Disease
Deletion of Abca7 Increases Cerebral Amyloid-β Accumulation in the J20 Mouse Model of Alzheimer's Disease
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DOI：
10.1523/jneurosci.4165-12.2013
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发表时间：
2013-03-06
影响因子：
5.3
通讯作者：
Garner, Brett
中科院分区：
文献类型：
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作者：
Kim, Woojin S.;Li, Hongyun;Garner, Brett
ATP结合盒转运蛋白A7（ABCA7）在脑中表达，并已在巨噬细胞、小胶质细胞和神经元中检测到。ABCA 7促进脂质从细胞流出到载脂蛋白，并且还可以调节吞噬作用并调节淀粉样前体蛋白（APP）的加工以产生阿尔茨海默病（AD）淀粉样β（A β）肽。全基因组关联研究表明，ABCA7单核苷酸多态性增加了迟发性AD的风险;然而，ABCA7在AD背景下在大脑中发挥的作用尚不清楚。在本研究中，我们将ABCA7缺陷（A7（-/-））小鼠与J20淀粉样蛋白生成小鼠杂交以解决这个问题。我们表明，ABCA7损失加倍不溶性A β水平和thiocaine-S阳性斑块在大脑中。这与APP加工的变化无关（通过分析全长APP和APP β C末端片段进行评估）。载脂蛋白E调节脑A β稳态和斑块负荷;然而，ABCA 7丢失并不改变载脂蛋白E浓度。与野生型小鼠相比，J20和J20/A7（-/-）小鼠的空间参考记忆均显著受损;然而，J20和J20/A7（-/-）小鼠之间没有认知差异。在J20和J20/A7（-/-）小鼠之间的海马或斑块相关小胶质细胞/巨噬细胞标志物中也没有检测到重大差异，而与野生型小鼠相比，来自A7（-/-）小鼠的骨髓源性巨噬细胞摄取寡聚体A β的能力降低了51%。我们的研究结果表明，ABCA 7在调节A β稳态在大脑中发挥作用，这可能与改变吞噬细胞功能。
ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected in macrophages, microglia, and neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins and can also regulate phagocytosis and modulate processing of amyloid precursor protein (APP) to generate the Alzheimer's disease (AD) amyloid-beta (A beta) peptide. Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown. In the present study, we crossed ABCA7-deficient (A7(-/-)) mice with J20 amyloidogenic mice to address this issue. We show that ABCA7 loss doubled insoluble A beta levels and thioflavine-S-positive plaques in the brain. This was not related to changes in APP processing (assessed by analysis of full-length APP and the APP beta C-terminal fragment). Apolipoprotein E regulates cerebral A beta homeostasis and plaque load; however, the apolipoprotein E concentration was not altered by ABCA7 loss. Spatial reference memory was significantly impaired in both J20 and J20/A7(-/-) mice compared with wild-type mice; however, there were no cognitive differences between J20 and J20/A7(-/-) mice. There were also no major differences detected in hippocampal or plaque-associated microglial/macrophage markers between J20 and J20/A7(-/-) mice, whereas the capacity for bone marrow-derived macrophages derived from A7(-/-) mice to take up oligomeric A beta was reduced by 51% compared with wild-type mice. Our results suggest that ABCA7 plays a role in the regulation of A beta homeostasis in the brain and that this may be related to altered phagocyte function.