Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier.
Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier.
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DOI：
10.1186/1742-2094-9-150
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发表时间：
2012-06-29
影响因子：
9.3
通讯作者：
Banks WA
中科院分区：
文献类型：
--
作者：
Erickson MA;Hartvigson PE;Morofuji Y;Owen JB;Butterfield DA;Banks WA
低密度脂蛋白受体相关蛋白-1（LRP-1）和P-糖蛋白（Pgp）从脑中清除淀粉样蛋白β（Aβ）的缺陷被认为是导致阿尔茨海默病（AD）的原因。我们最近发现脂多糖（LPS）诱导的全身性炎症导致Aβ从脑中流出受损。同样的治疗也会损害Pgp功能。在此，我们的目的是确定全身性炎症后Aβ清除的哪些生理途径受到影响，包括依赖于血脑屏障中LRP-1和Pgp功能的途径。在0、6和24小时对6至8周龄的CD-1小鼠进行3次腹腔注射3 mg/kg LPS，并在28小时进行研究。将125 I-A β1-42或125 I-alpha-2-巨球蛋白注射到大脑侧脑室（脑室内（ICV））或颈静脉（静脉内（IV））中，用于量化脑血管系统和脑实质之间的LRP-1依赖性分配以及外周清除率。测量ICV注射的14 C-菊糖从脑中的消失以定量脑脊液（CSF）的整体流量。免疫印迹法检测LRP-1和Pgp的脑微血管蛋白表达。用免疫荧光显微镜检测内皮细胞LRP-1的定位。通过LRP-1的免疫沉淀，随后通过4-羟基壬烯醛和3-硝基酪氨酸的免疫印迹来测量脑微血管中对LRP-1的氧化修饰。我们发现LPS：导致ICV注射的Aβ从脑实质向脑血管系统的LRP-1依赖性再分布，并减少进入血液; IV注射的Aβ的外周清除受损;抑制CSF的重吸收;未显著改变LRP-1或Pgp的脑微血管蛋白水平或LRP-1的氧化修饰;下调LRP-1蛋白水平并导致LRP-1在培养的脑内皮细胞中的错误定位。这些结果表明，LRP-1经历复杂的功能调节后，全身炎症，这可能取决于细胞类型，亚细胞位置，和翻译后修饰。我们的研究结果表明，全身性炎症导致Aβ转运和整体流动的缺陷，就像在AD中观察到的那样，表明炎症可以诱导和促进疾病。
Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aβ) from brain are thought to contribute to Alzheimer’s disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood–brain barrier. CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aβ1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells. These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aβ transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease.
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影响因子：
15.1
作者：
Erickson, Michelle A.;Banks, William A.
通讯作者：
Banks, William A.
影响因子：
4.1
作者：
GREENWOOD, FC;HUNTER, WM
通讯作者：
HUNTER, WM
影响因子：
82.9
作者：
Deane, R;Yan, SD;Zlokovic, B
通讯作者：
Zlokovic, B
影响因子：
6.3
作者：
Hawkins, Brian T.;Rigor, Robert R.;Miller, David S.
通讯作者：
Miller, David S.
影响因子：
3.3
作者：
Banks, WA;Robinson, SM;Morley, JE
通讯作者：
Morley, JE