Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt-Jakob disease.
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 (PrP(Sc)) 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 PrP(Sc) either by promoting the buildup of Abeta (which could act as a seed for the aggregation of PrP(Sc)), 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.
Vogelgesang
Silke
S
Department of Neuropathology, University of Greifswald, 17487, Greifswald, Germany. sivogelg@uni-greifswald.de
Glatzel
Markus
M
Walker
Lary C
LC
Kroemer
Heyo K
HK
Aguzzi
Adriano
A
Warzok
Rolf W
RW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1