Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease.
Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease.
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DOI：
10.1016/j.bbi.2009.01.017
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发表时间：
2009-05
影响因子：
15.1
通讯作者：
Banks, William A.
中科院分区：
文献类型：
--
作者：
Jaeger, Laura B.;Dohgu, Shinya;Sultana, Rukhsana;Lynch, Jessica L.;Owen, Joshua B.;Erickson, Michelle A.;Shah, Gul N.;Price, Tulin O.;Fleegal-Demotta, Melissa A.;Butterfiled, D. Allan;Banks, William A.
关键词：
阿尔茨海默病(AD)的大脑以淀粉样蛋白(Aβ)积聚和神经炎症为特征。增加血到脑的内流和减少脑到血的跨血脑屏障(BBB)外流被认为是Aü蓄积的机制。流行病学研究表明，非类固醇抗炎药(NSAID)吲哚美辛可以减缓AD的进展。我们假设炎症改变了血脑屏障对A？的处理。脂多糖处理的小鼠增加了脑内流，减少了Aβ的脑外流，这是对AD的研究结果的总结。内毒素不能直接作用于BBB细胞，也不能直接调节BBB细胞的内流和外流。内流的增加是由一种血液传播因子介导的，该因子不依赖吲哚美辛，被甘油三酯阻断，与血到脑的转运蛋白Aü，RAGE的表达无关。血清IL-6、IL-10、IL-13和MCP-1水平反映了A？吲哚美辛可阻断外流减少，并伴随脑到血转运蛋白Aç，LRP-1蛋白表达的降低。内毒素反常地增加神经元LRP-1的表达，而LRP-1是Aü的主要来源。因此，炎症通过增加内流、减少外流和增加神经元产生三种机制潜在地增加大脑中Aü的水平。
Alzheimer’s disease (AD) brains are characterized by accumulation of amyloid-ß protein (Aβ) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Aß accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Aß. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Aβ, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Aß, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Aß influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Aß, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Aß. Thus, inflammation potentially increases brain levels of Aß by three mechanisms: increased influx, decreased efflux, and increased neuronal production.
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