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

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Abstract

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 β-amyloid protein (Aβ) 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 Aβ, 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, Aβ 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 Aβ (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.

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Acknowledgments

We thank S. Uffmann, A. Wolter, and C. Mueller for excellent technical assistance.

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Authors and Affiliations

  1. Department of Neuropathology, University of Greifswald, F.-Loeffler-Str. 23 e, 17487, Greifswald, Germany

    Silke Vogelgesang & Rolf W. Warzok

  2. Department of Neuropathology, University of Hamburg, Hamburg, Germany

    Markus Glatzel

  3. Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA, USA

    Lary C. Walker

  4. Department of Pharmacology, University of Greifswald, Greifswald, Germany

    Heyo K. Kroemer

  5. Department of Neuropathology, University of Zurich, Zurich, Switzerland

    Adriano Aguzzi

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  1. Silke Vogelgesang
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  2. Markus Glatzel
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  3. Lary C. Walker
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  4. Heyo K. Kroemer
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  5. Adriano Aguzzi
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Correspondence to Silke Vogelgesang.

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Vogelgesang, S., Glatzel, M., Walker, L.C. et al. Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt–Jakob disease. Acta Neuropathol 111, 436–443 (2006). https://doi.org/10.1007/s00401-006-0042-3

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