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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Saint Louis University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
McNulty, Erin; Selariu, Anca I; Anderson, Kelly et al. (2016) Aspects of the husbandry and management of captive cervids. Lab Anim (NY) 45:140-2
Urayama, Akihiko; Grubb, Jeffrey H; Sly, William S et al. (2016) Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier. J Cereb Blood Flow Metab 36:476-86
Banks, William A; Niehoff, Michael L; Ponzio, Nicholas M et al. (2012) Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice. J Neuroinflammation 9:231
Dohgu, Shinya; Fleegal-DeMotta, Melissa A; Banks, William A (2011) Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF. J Neuroinflammation 8:167
Urayama, Akihiko; Morales, Rodrigo; Niehoff, Michael L et al. (2011) Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake. FASEB J 25:2792-803
Banks, William A (2010) Mouse models of neurological disorders: a view from the blood-brain barrier. Biochim Biophys Acta 1802:881-8
Salkeni, Mohamad A; Lynch, Jessica L; Otamis-Price, Tulin et al. (2009) Lipopolysaccharide impairs blood-brain barrier P-glycoprotein function in mice through prostaglandin- and nitric oxide-independent pathways. J Neuroimmune Pharmacol 4:276-82
Hawkins, Patrick M; Jelliss, Paul A; Nonaka, Naoko et al. (2009) Permeability of the blood-brain barrier to a rhenacarborane. J Pharmacol Exp Ther 329:608-14
Banks, W A; Robinson, Sandra M; Diaz-Espinoza, R et al. (2009) Transport of prion protein across the blood-brain barrier. Exp Neurol 218:162-7
Jaeger, Laura B; Dohgu, Shinya; Sultana, Rukhsana et al. (2009) Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease. Brain Behav Immun 23:507-17

Showing the most recent 10 out of 20 publications