title: Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease.
abstract: Alzheimer's disease (AD) brains are characterized by accumulation of amyloid beta protein (Abeta) 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 Abeta 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 Abeta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Abeta, 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 Abeta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Abeta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Abeta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Abeta. Thus, inflammation potentially increases brain levels of Abeta by three mechanisms: increased influx, decreased efflux, and increased neuronal production.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Jaeger
authors.forename: Shinya
authors.initials: S
authors.lastname: Dohgu
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Lynch
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Owen
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Erickson
authors.forename: Gul N
authors.initials: GN
authors.lastname: Shah
authors.forename: Tulin O
authors.initials: TO
authors.lastname: Price
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Fleegal-Demotta
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfiled
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects* / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D014304:Triolein / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D014304:Triolein; D007213:Indomethacin