NR AUSH
AU Vogelgesang,S.; Glatzel,M.; Walker,L.C.; Kroemer,H.K.; Aguzzi,A.; Warzok,R.W.
TI Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt-Jakob disease
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Pathogenese/Infektion PATH-08
PT Konferenz-Poster
AB The abnormal conformation and assembly of proteins in the central nervous system is increasingly thought to be a critical pathogenic mechanism in neurodegenerative disorders such as Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). CJD is marked primarily by the buildup of misfolded prion protein (PrPsc) in brain, whereas the accrual of ß-amyloid protein (Aß) and tau protein are characteristic for AD. Prior studies have shown that the ATP-binding cassette transporter P-glycoprotein (P-gp) is a cellular efflux pump for Aß, and that age-associated deficits in P-gp may be involved in the pathogenesis of Alzheimer's disease. In the present study, we investigated the relationship between P-gp and idiopathic CJD, and found that CJD, like AD, is associated with a decrease in the expression of cerebrovascular P-gp. In some instances, Aß and PrP deposits coexist in cases of CJD, suggesting the possibility of pathogenic interactions. Since there is, to date, no evidence that PrP itself is a substrate for P-gp, we hypothesize that the age-related deficits in P-gp could promote the accumulation of PrPsc either by promoting the buildup of Aß (which could act as a seed for the aggregation of PrPsc), or by overloading the ubiquitin-proteasomal catabolic system, and thereby facilitating the accumulation of PrP. Alternatively, the loss of P-gp could be a nonspecific response to neurodegenerative changes in the central nervous system. In either case, dysfunction of this critical toxin-elimination pathway in CJD and AD suggests that selectively increasing cerebrovascular P-gp function could open new therapeutic pathways for the prevention and/or treatment of a number of proteopathic disorders of the central nervous system.
AD Silke Vogelgesang, Rolf W. Warzok, Department of Neuropathology, University of Greifswald, Germany; Markus Glatzel, Department of Neuropathology, University of Hamburg, Germany; Lary C. Walker, Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA, USA; Heyo K. Kroemer, Department of Pharmacology, University of Greifswald, Germany; Adriano Aguzzi, Department of Neuropathology, University of Zuerich, Switzerland
SP englisch
PO Deutschland