title: Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology and Physiology, Saint Louis University, 1402 South Grand Blvd, St. Louis, MO 63104, USA.
authors: Michelle A
authors: MA
authors: Erickson
authors: Pehr E
authors: PE
authors: Hartvigson
authors: Yoichi
authors: Y
authors: Morofuji
authors: Joshua B
authors: JB
authors: Owen
authors: D Allan
authors: DA
authors: Butterfield
authors: William A
authors: WA
authors: Banks
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000378:metabolism*; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)