Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt-Jakob disease

被引:32
作者
Vogelgesang, S
Glatzel, M
Walker, LC
Kroemer, HK
Aguzzi, A
Warzok, RW
机构
[1] Univ Greifswald, Dept Neuropathol, D-17487 Greifswald, Germany
[2] Univ Hamburg, Dept Neuropathol, Hamburg, Germany
[3] Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA
[4] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA
[5] Univ Greifswald, Dept Pharmacol, D-17487 Greifswald, Germany
[6] Univ Zurich, Dept Neuropathol, Zurich, Switzerland
关键词
Creutzfeldt-Jakob disease; cerebral amyloid angiopathy; P-glycoprotein; prion; proteopathies; beta-amyloid; Alzheimer's disease;
D O I
10.1007/s00401-006-0042-3
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 (A beta) 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 A beta, 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, A beta 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 A beta (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.
引用
收藏
页码:436 / 443
页数:8
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