Prion Transport Across the Blood-Brain Barrier

Summary

Principal Investigator: William Banks
Affiliation: Saint Louis University
Country: USA
Abstract: Prion diseases represent a diverse group of infectious neurodegenerative disorders. The most accepted hypothesis is that the infectious agent (termed prion) is a misfolded version of a normal protein completely devoid of nucleic acids. Disease is propagated when the infectious form (PrPsc) converts the normal form (PrPc) to the infectious form by reversibly combining with it. In scrapie, the prion is a glycoprotein with about a 30,000 MW protein core. To produce central nervous system (CNS) disease, PrPsc must enter the brain, which requires it negotiate the blood-brain barrier (BBB). The major goal of this research is to determine how PrPsc crosses the BBB and ultimately to develop therapeutic strategies for blocking passage into the CNS and so preventing prion disease. Work by us and others have shown that other neurotoxic glycoproteins (such as wheatgerm agglutinin and gp120, the coat of the AIDS virus) cross the BBB by inducing absorptive endocytosis (AE). We hypothesize that PrPsc crosses the BBBthrough the mechanism of AE. This hypothesis provides a mechanism for passage across the BBB of cell-free PrPsc and of PrPsc- infected immune cells and explains how some regions of the CNS, such as the thoracic spinal cord, can be especially targeted. Although our working hypothesis is that cell-free PrPsc is the major mechanism , these experiments are designed to determine the extent to which the other possible mechanisms of entry into the CNS (immune cell transfer, retrograde splenic nerve transmission, transmembrane diffusion, saturable carrier/receptor mediated transport, leakage via extracellular pathways) are operational for PrPsc. We will use highly purified, radioactively labeled PrPsc to determine rates of transport and distribution into brain regions, spinal cord, and CSF, the role of splenic nerves and immune cells in neuroinvasion, and in vitro models to examine the cellular biology of passage across the brain endothelial cell. Lay Summary: Prions cause rare, but devastating, diseases such as mad cow disease. To cause disease, prions must cross the blood-brain barrier to enter the brain. We will determine how prions cross the BBB. Knowing how prions enter the brain should lead to strategies on how to prevent prion diseases.
Funding Period: 2006-08-15 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice
    William A Banks
    GRECC, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
    J Neuroinflammation 9:231. 2012
  2. pmc Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF
    Shinya Dohgu
    Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
    J Neuroinflammation 8:167. 2011
  3. pmc Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake
    Akihiko Urayama
    Department of Neurology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA
    FASEB J 25:2792-803. 2011
  4. pmc Mouse models of neurological disorders: a view from the blood-brain barrier
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, 915 N Grand Blvd, St Louis, MO 63106, USA
    Biochim Biophys Acta 1802:881-8. 2010
  5. pmc Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity
    Eran Elinav
    Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
    Endocrinology 150:3083-91. 2009
  6. pmc The blood-brain barrier: connecting the gut and the brain
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, WAB, 915 N Grand Blvd, St Louis, MO 63106, USA
    Regul Pept 149:11-4. 2008
  7. pmc Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease: an age-related selective uptake with reversal of learning impairment
    William A Banks
    Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center St Louis, MO 63106, USA
    Exp Neurol 206:248-56. 2007
  8. ncbi Brain-immune communication pathways
    Ning Quan
    Institute of Behavioral Medicine, Ohio State University, USA
    Brain Behav Immun 21:727-35. 2007
  9. doi Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins
    Naoko Nonaka
    Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, John Cochran Division, 915 N Grand Blvd, St Louis, MO 63106, USA
    J Pharmacol Exp Ther 325:513-9. 2008
  10. pmc Nitric oxide activity and isoenzyme expression in the senescence-accelerated mouse p8 model of Alzheimer's disease: effects of anti-amyloid antibody and antisense treatments
    Abbas K Ali
    Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center St Louis, MO 63106, USA
    J Gerontol A Biol Sci Med Sci 64:1025-30. 2009

Scientific Experts

  • Akihiko Urayama
  • Jessica L Lynch
  • William Banks
  • Shinya Dohgu
  • MELISSA A FLEEGAL-DEMOTTA
  • Laura B Jaeger
  • Susan A Farr
  • Naoko Nonaka
  • Gul N Shah
  • Patrick M Hawkins
  • Eran Elinav
  • Vijaya B Kumar
  • Mohamad A Salkeni
  • Abbas K Ali
  • Tulin O Price
  • Ning Quan
  • Xiaoming Shi
  • Mark C Hwang
  • Michael L Niehoff
  • Steven N Johnson
  • M Paul Murphy
  • D Allan Butterfield
  • D Allan Butterfiled
  • Shay Reicher
  • John E Morley
  • Sandra M Robinson
  • Mohammed Ali
  • Tulin Otamis-Price
  • Michal Yacobovitz
  • Arieh Gertler
  • Leonora Niv-Spector
  • Gili Solomon
  • Rukhsana Sultana
  • Paul A Jelliss
  • Joshua B Owen
  • Meirav Katz
  • Michelle A Erickson
  • Zamir Halpern
  • Haruaki Kageyama
  • Seiji Shioda

Detail Information

Publications18

  1. pmc Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice
    William A Banks
    GRECC, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
    J Neuroinflammation 9:231. 2012
    ..Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell-tissue interactions...
  2. pmc Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF
    Shinya Dohgu
    Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
    J Neuroinflammation 8:167. 2011
    ..These cytokines, in turn, act at the luminal surface of the BMEC to enhance the transcellular transport of HIV-1 independently of actions on paracellular permeability...
  3. pmc Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake
    Akihiko Urayama
    Department of Neurology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA
    FASEB J 25:2792-803. 2011
    ..Our results provide a fundamental pharmacokinetic characterization of PrP(Sc) in vivo, which may be relevant to estimate tissue risks and mechanisms of prion neuroinvasion and to identify novel therapeutic strategies...
  4. pmc Mouse models of neurological disorders: a view from the blood-brain barrier
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, 915 N Grand Blvd, St Louis, MO 63106, USA
    Biochim Biophys Acta 1802:881-8. 2010
    ..An increasing number of diseases are so categorized in which BBB dysfunction or dysregulation plays a major role; this review highlights such roles for the BBB including those proposed for Alzheimer's disease and obesity...
  5. pmc Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity
    Eran Elinav
    Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
    Endocrinology 150:3083-91. 2009
    ..This compound should be useful in exploring the involvement of leptin in metabolic and immune processes and could serve as a therapeutic for the treatment of cachexia...
  6. pmc The blood-brain barrier: connecting the gut and the brain
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, WAB, 915 N Grand Blvd, St Louis, MO 63106, USA
    Regul Pept 149:11-4. 2008
    ..By these and other mechanisms, the BBB regulates communications between the CNS and GI tract...
  7. pmc Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease: an age-related selective uptake with reversal of learning impairment
    William A Banks
    Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center St Louis, MO 63106, USA
    Exp Neurol 206:248-56. 2007
    ..In conclusion, an IgM antibody was produced that crosses the BBB to reverse cognitive impairment in a murine model of Alzheimer's disease...
  8. ncbi Brain-immune communication pathways
    Ning Quan
    Institute of Behavioral Medicine, Ohio State University, USA
    Brain Behav Immun 21:727-35. 2007
    ..These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another...
  9. doi Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins
    Naoko Nonaka
    Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, John Cochran Division, 915 N Grand Blvd, St Louis, MO 63106, USA
    J Pharmacol Exp Ther 325:513-9. 2008
    ..These studies show that intranasal administration is an effective route of administration for the delivery of GALP to the brain and that targeting among brain regions may be possible with the use of various cyclodextrins...
  10. pmc Nitric oxide activity and isoenzyme expression in the senescence-accelerated mouse p8 model of Alzheimer's disease: effects of anti-amyloid antibody and antisense treatments
    Abbas K Ali
    Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center St Louis, MO 63106, USA
    J Gerontol A Biol Sci Med Sci 64:1025-30. 2009
    ..These results suggest a complex relation between Abeta and NOS in the SAMP8 that is largely mediated through posttranslational mechanisms...
  11. pmc Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease
    Laura B Jaeger
    Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO 63104, USA
    Brain Behav Immun 23:507-17. 2009
    ..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...
  12. pmc Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition
    Laura B Jaeger
    Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO, USA
    J Alzheimers Dis 17:553-70. 2009
    ..These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Abeta could increase and AD would be promoted...
  13. pmc Transport of prion protein across the blood-brain barrier
    W A Banks
    GRECC, Veterans Affairs Medical Center St Louis, MO, USA
    Exp Neurol 218:162-7. 2009
    ..These results show that PrP(c) has bidirectional, saturable transport across the BBB and selectively targets some CNS regions. Such transport may play a role in PrP(c) function and prion replication...
  14. pmc Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway
    Shinya Dohgu
    Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center St Louis, and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri 63106, USA
    Exp Neurol 210:740-9. 2008
    ..These results show that LPS increases HIV-1 transcellular transport across the BBB by a pathway that is mediated by p38 MAPK phosphorylation in BMECs...
  15. pmc Permeability of the blood-brain barrier to a rhenacarborane
    Patrick M Hawkins
    Saint Louis University School of Medicine, St Louis, Missouri, USA
    J Pharmacol Exp Ther 329:608-14. 2009
    ..This supports their use as therapeutic agents for targeting the central nervous system...
  16. pmc Lipopolysaccharide impairs blood-brain barrier P-glycoprotein function in mice through prostaglandin- and nitric oxide-independent pathways
    Mohamad A Salkeni
    Department of Internal Medicine, Division of Geriatrics, Saint Louis University School of Medicine, St Louis, USA
    J Neuroimmune Pharmacol 4:276-82. 2009
    ..We conclude that induction of proinflammatory states as exemplified by LPS treatment can inhibit P-gp function in vivo at the blood-brain barrier...
  17. ncbi Opiate modulation of IL-1alpha, IL-2, and TNF-alpha transport across the blood-brain barrier
    Jessica L Lynch
    GRECC, Veterns Affairs Medical Center St Louis and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, C O Dr William Banks Laboratory, 915 N, Grand Boulevard, St Louis, MO 63106, USA
    Brain Behav Immun 22:1096-102. 2008
    ..Whereas IL-1alpha, IL-2, and TNF-alpha are all proinflammatory cytokines, morphine exposure has individualized effects on their blood-to-brain transport...
  18. ncbi Insulin resistance syndrome in the elderly: assessment of functional, biochemical, metabolic, and inflammatory status
    William A Banks
    Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, St Louis, Missouri, USA
    Diabetes Care 30:2369-73. 2007
    ..Here, we determined the impact of IRS on functional, biochemical, metabolic, and inflammatory status in a high-risk population: elderly women in nursing homes...