Altered clearance of beta-amyloid from the cerebrospinal fluid following subchronic lead exposure in rats: Roles of RAGE and LRP1 in the choroid plexus.
Altered clearance of beta-amyloid from the cerebrospinal fluid following subchronic lead exposure in rats: Roles of RAGE and LRP1 in the choroid plexus.
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DOI：
10.1016/j.jtemb.2020.126520
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发表时间：
2020-04-08
期刊：
影响因子：
--
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Shen X;Xia L;Liu L;Jiang H;Shannahan J;Du Y;Zheng W
淀粉样斑块的形成是阿尔茨海默病的标志。我们的早期研究表明，PDAPP转基因小鼠的铅（Pb）暴露增加了脑脊液（CSF）和海马中的β-淀粉样蛋白（Aβ）水平，导致小鼠脑中淀粉样蛋白斑块的形成。CSF中的Aβ受脉络丛中的血-CSF屏障（BCB）调节。然而，关于铅暴露是否以及如何影响BCB中Aβ的流入和流出的问题仍然未知。本研究旨在研究铅暴露是否改变了脉络丛中Aβ从CSF到血液的流出，以及铅如何影响两种主要Aβ转运蛋白的表达和亚细胞易位，即，脉络丛中的晚期糖基化终产物受体（RECEPTOR）和低密度脂蛋白受体蛋白-1（LRP 1）。Sprague-Dawley大鼠每日灌胃0、14（低剂量）和27（高剂量）mg Pb/kg醋酸铅，5 d/wk，连续4或8 wk，染毒结束后经颈内动脉注入含Aβ40（2.5 μg/mL）的溶液。ELISA法显示，两种剂量的亚慢性铅暴露均显著增加了CSF和脉络丛中的Aβ水平（p<0.05）。共聚焦数据显示，4周的铅暴露促使亚细胞易位的cytokine从脉络膜细胞质向顶端微绒毛。此外，在低剂量和高剂量组中，它分别使脉络丛中的cDNA 3表达比对照增加34.1%和25.1%（p<0.05）。亚慢性铅暴露对LRP 1的表达没有显著影响，但高剂量组显示LRP 1沿着基底层聚集。脑室-脑池灌注的数据显示，Aβ40从CSF通过血-CSF屏障向血液的流出量显著降低。孵育新鲜解剖的神经丛组织与铅在人工脑脊液支持铅的影响，增加表达。综上所述，这些数据表明，亚慢性暴露后脉络丛中的铅蓄积减少了脉络丛对Aβ从CSF到血液的清除，进而导致CSF中Aβ的增加。铅与脉络膜上皮细胞中的LRP 1和E2的相互作用可能有助于改变Aβ通过脑室血-CSF屏障的转运。
Formation of amyloid plaques is the hallmark of Alzheimer’s disease. Our early studies show that lead (Pb) exposure in PDAPP transgenic mice increases β-amyloid (Aβ) levels in the cerebrospinal fluid (CSF) and hippocampus, leading to the formation of amyloid plaques in mouse brain. Aβ in the CSF is regulated by the blood-CSF barrier (BCB) in the choroid plexus. However, the questions as to whether and how Pb exposure affected the influx and efflux of Aβ in BCB remained unknown. This study was conducted to investigate whether Pb exposure altered the Aβ efflux in the choroid plexus from the CSF to blood, and how Pb may affect the expression and subcellular translocation of two major Aβ transporters, i.e., the receptor for advanced glycation end-products (RAGE) and the low density lipoprotein receptor protein-1 (LRP1) in the choroid plexus. Sprague-Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ40 (2.5 μg/mL) was infused to rat brain via a cannulated internal carotid artery. Subchronic Pb exposure at both dose levels significantly increased Aβ levels in the CSF and choroid plexus (p<0.05) by ELISA. Confocal data showed that 4-wk Pb exposures prompted subcellular translocation of RAGE from the choroidal cytoplasm toward apical microvilli. Furthermore, it increased the RAGE expression in the choroid plexus by 34.1% and 25.1% over the controls (p<0.05) in the low- and high- dose groups, respectfully. Subchronic Pb exposure did not significantly affect the expression of LRP1; yet the high-dose group showed LRP1 concentrated along the basal lamina. The data from the ventriculo-cisternal perfusion revealed a significantly decreased efflux of Aβ40 from the CSF to blood via the blood-CSF barrier. Incubation of freshly dissected plexus tissues with Pb in artificial CSF supported a Pb effect on increased RAGE expression. Taken together, these data suggest that Pb accumulation in the choroid plexus after subchronic exposure reduces the clearance of Aβ from the CSF to blood by the choroid plexus, which, in turn, leads to an increase of Aβ in the CSF. Interaction of Pb with RAGE and LRP1 in choroidal epithelial cells may contribute to the altered Aβ transport by the blood-CSF barrier in brain ventricles.
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