Uptake of Aβ by OATPs Might Be a New Pathophysiological Mechanism of Alzheimer Disease
Uptake of Aβ by OATPs Might Be a New Pathophysiological Mechanism of Alzheimer Disease
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OATPs 对 Aβ 的摄取可能是阿尔茨海默病的新病理生理机制
DOI：
10.21203/rs.3.rs-125629/v1
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
YanNi Lv
中科院分区：
文献类型：
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作者：
JinHua Wen;MengHua Zhao;Ying Zhou;YanNi Lv
背景神经毒性淀粉样β蛋白(Aβ)在脑内的蓄积是阿尔茨海默病(AD)的一个特征。在过去的十年里，一些报道表明P-糖蛋白(由ABCB1编码)积极地介导Aβ多肽的外流转运。然而，Aβ多肽进入细胞的机制尚不清楚。我们发现AD小鼠肝组织中有机阴离子转运多肽2(Oatp2)的蛋白表达明显高于正常小鼠。相比之下，阿尔茨海默病小鼠大脑中Oatp2的蛋白表达显著减少。OATP1B1作为一种重要的药物转运体，可能与AD的病理生理机制有关。结果在本研究中，我们建立了OATP1B1-GFP-HEK293T细胞模型，证实了OATP1B1介导的β1-42转运。与c对照组相比，OATP1B1-GFP-HEK293T组Aβ1-42蛋白摄取量随着Aβ1-42浓度的增加而显著增加，且随着孵育时间的延长而显著增加。流式细胞仪检测结果相似，HEK239T-OATP1B1细胞对Aβ1-42的摄取几乎是对照组的两倍。这些结果表明，OATP1B1是Aβ1-42从血液到组织(包括肝脏和大脑)运输的重要“载体”。结论OATP1B1是一项新颖而有趣的发现，OATP1B1可作为治疗AD的新靶点。
BackgroundThe accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD). Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABCB1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. We found that the protein expression oforganic anion transporting Polypeptide 2 (Oatp2) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp2 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD. ResultsIn this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport ofAβ1-42.Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK239T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATP1B1 acts as an important “carrier” for the transport of Aβ1-42 from the blood to the tissues, including liver and brain. ConclusionsThis is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.