Fu YuHong, Hsiao Jen-Hsiang T, Paxinos George, Halliday Glenda M, Kim Woojin Scott
Neuroscience Research Australia, Sydney, NSW, Australia.
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
J Alzheimers Dis. 2016 Sep 6;54(2):569-84. doi: 10.3233/JAD-160456.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为痴呆以及大脑中淀粉样β蛋白聚集体的异常沉积。最近的全基因组关联研究表明，ABCA7与AD密切相关。体外证据表明，ABCA7的作用与吞噬活性有关。在AD小鼠模型中删除ABCA7会加剧脑淀粉样β斑块负荷。然而，ABCA7在AD脑发病机制中的生物学作用尚不清楚。我们发现，ABCA7在小胶质细胞以及单核细胞分化为巨噬细胞时高表达。我们推测，ABCA7在大脑中发挥保护作用，与淀粉样β蛋白的吞噬清除有关。我们从Abca7基因敲除小鼠和野生型小鼠中分离出小胶质细胞和巨噬细胞，并测试它们吞噬淀粉样β寡聚体的能力。我们发现，与野生型小鼠相比，Abca7基因敲除小鼠的小胶质细胞和巨噬细胞中淀粉样β蛋白的吞噬清除均显著减少。与这些结果一致，Abca7基因敲除小鼠海马体中淀粉样β寡聚体的体内吞噬清除减少。此外，在AD脑以及特别是在海马体中发生淀粉样病变的小鼠脑中，作为对淀粉样β致病状态的反应，ABCA7转录上调。这些结果共同表明，ABCA7介导大脑中淀粉样β蛋白的吞噬清除，并揭示了ABCA7功能丧失增加AD易感性的机制。
