Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2012-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/9/1/150 |
| _version_ | 1818472691003293696 |
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| author | Erickson Michelle A Hartvigson Pehr E Morofuji Yoichi Owen Joshua B Butterfield D Banks William A |
| author_facet | Erickson Michelle A Hartvigson Pehr E Morofuji Yoichi Owen Joshua B Butterfield D Banks William A |
| author_sort | Erickson Michelle A |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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. <sup>125</sup>I-Aβ<sub>1-42</sub> or <sup>125</sup>I-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 <sup>14</sup> 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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p> |
| first_indexed | 2024-04-14T04:12:04Z |
| format | Article |
| id | doaj.art-bf220420142b407eb97e8c4d4baf2e95 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-14T04:12:04Z |
| publishDate | 2012-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-bf220420142b407eb97e8c4d4baf2e952022-12-22T02:13:07ZengBMCJournal of Neuroinflammation1742-20942012-06-019115010.1186/1742-2094-9-150Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrierErickson Michelle AHartvigson Pehr EMorofuji YoichiOwen Joshua BButterfield DBanks William A<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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. <sup>125</sup>I-Aβ<sub>1-42</sub> or <sup>125</sup>I-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 <sup>14</sup> 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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p>http://www.jneuroinflammation.com/content/9/1/150Alzheimer’s diseaseamyloid betablood–brain barrierinflammationlipopolysaccharideLRP1PgpABCB1MDR1cerebrospinal fluid |
| spellingShingle | Erickson Michelle A Hartvigson Pehr E Morofuji Yoichi Owen Joshua B Butterfield D Banks William A Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier Journal of Neuroinflammation Alzheimer’s disease amyloid beta blood–brain barrier inflammation lipopolysaccharide LRP1 Pgp ABCB1 MDR1 cerebrospinal fluid |
| title | Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier |
| title_full | Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier |
| title_fullStr | Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier |
| title_full_unstemmed | Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier |
| title_short | Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier |
| title_sort | lipopolysaccharide impairs amyloid beta efflux from brain altered vascular sequestration cerebrospinal fluid reabsorption peripheral clearance and transporter function at the blood brain barrier |
| topic | Alzheimer’s disease amyloid beta blood–brain barrier inflammation lipopolysaccharide LRP1 Pgp ABCB1 MDR1 cerebrospinal fluid |
| url | http://www.jneuroinflammation.com/content/9/1/150 |
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