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. 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
  2. ncbi 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
  3. ncbi 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
  4. ncbi 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
  5. ncbi 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
  6. ncbi 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
  7. 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
  8. ncbi 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
  9. ncbi 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
  10. ncbi 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

Scientific Experts

  • William Banks
  • Jessica L Lynch
  • Laura B Jaeger
  • Shinya Dohgu
  • MELISSA A FLEEGAL-DEMOTTA
  • Susan A Farr
  • Naoko Nonaka
  • Vijaya B Kumar
  • Gul N Shah
  • Mohamad A Salkeni
  • Abbas K Ali
  • Patrick M Hawkins
  • Ning Quan
  • Tulin Otamis-Price
  • Xiaoming Shi
  • Mark C Hwang
  • Michael L Niehoff
  • Steven N Johnson
  • M Paul Murphy
  • D Allan Butterfield
  • D Allan Butterfiled
  • Tulin O Price
  • Rukhsana Sultana
  • John E Morley
  • Paul A Jelliss
  • Joshua B Owen
  • Sandra M Robinson
  • Michelle A Erickson
  • Haruaki Kageyama
  • Seiji Shioda

Detail Information

Publications13

  1. 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...
  2. ncbi 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...
  3. ncbi 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...
  4. ncbi 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...
  5. ncbi 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...
  6. ncbi 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...
  7. 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...
  8. ncbi 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...
  9. ncbi 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...
  10. ncbi 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...
  11. 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...
  12. ncbi 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...
  13. ncbi 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...