NR AVTY
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 Acta Neuropathologica 2006 May; 111(5): 436-43
PT journal article
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 beta-amyloid protein (Abeta) 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 Abeta, 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, Abeta 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 Abeta (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 non-specific 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.
MH Aged; Aged, 80 and over; Alzheimer Disease/metabolism/pathology; Cerebral Amyloid Angiopathy/metabolism/pathology; Cerebral Arteries/*metabolism/pathology; Creutzfeldt-Jakob Syndrome/*metabolism/pathology; Down-Regulation/genetics; Female; Gene Expression Regulation; Humans; Male; Middle Aged; P-Glycoprotein/genetics/*metabolism; Prion Diseases/metabolism/pathology
AD Department of Neuropathology, University of Greifswald, 17487, Greifswald, Germany. sivogelg@uni-greifswald.de
SP englisch
PO Deutschland