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From: TSS ()
Acta Neuropathol (2006) DOI 10.1007/s00401-006-0042-3 Silke Vogelgesang Ć Markus Glatzel Ć Lary C. Walker Heyo K. Kroemer Ć Adriano Aguzzi Ć Rolf W. Warzok Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt–Jakob disease Received: 21 November 2005 / Accepted: 19 December 2005 Springer-Verlag 2006 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 b-amyloid protein (Ab) 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 Ab, 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, Ab 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 Ab (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. snip... There are several potential means by which P-gp function might be related to prion disease. One possibility is that P-gp could be down-regulated in the brain as a result of the disease process, i.e., that P-gp expression loss is a consequence rather than a cause of PrP accumulation. Longitudinal studies of P-gp expression in PrP-transgenic mice, which do not deposit Ab with age, would help to establish whether P-gp function declines before, or after, the onset of disease phenotype. Another possibility is that the loss of P-gp is a causative factor in the accumulation of PrP in brain. The age-associated loss of P-gp function [45] suggests one means whereby age might influence the risk of CJD. To date, there is no evidence that PrP itself is a substrate for P-gp, but there are two general, alternative pathways through which P-gp reduction might stimulate the accumulation and subsequent toxicity of PrPSc. First, the loss of P-gp function could facilitate the buildup of Ab, which then acts as a heterologous seed for the aggregation of PrPSc. Ab deposition frequently is found in TSE, including CJD [8], although at present it is uncertain whether Ab accumulation is pathogenically linked to prion disease, or whether it is an independent (e.g., age-related) process. Interestingly, the levels of Ab42 are decreased in the CSF of patients with CJD, similar to the reduction seen in patients with AD [32, 50]. Other studies have reported a colocalization of Ab and PrP in the same plaques in CJD cases, suggesting that preexisting b-amyloid might augment PrP accumulation by promoting the aggregation of one amyloidogenic protein (PrPSc) onto a core composed of the other (Ab) [21, 27]. Our results confirm that PrP can decorate the periphery of Ab plaques. We also observed the converse, i.e., that Ab can deposit on PrP plaque cores. Occasionally, there were even multilayered plaques, with central Ab deposition, a rim of PrP and an outer accumulation of Ab. Furthermore, there were rare blood vessels with mural colocalisation of Ab and PrP. These results suggest that both proteins interact Table 3 Mean middle optic density (mod) value of P-gp expression in Ab-positive and negative CJD cases P-gp (mod) Ab42+(n=5) Ab42-(n=5) P Ab40+(n=4) Ab40-(n=6) P Cortex 7.52 4.35 0.69 6.39 4.68 0.91 Leptomeninx 0.77 0.70 0.69 1.11 0.70 0.83 Fig. 3 Immunohistochemical double-labeling of Ab (brown) and PrP (red) in Creutzfeldt– Jakob cases. a Plaque with an Ab core and a PrP shell. b Plaque with a PrP core and an Ab shell. c Plaque with central Ab deposition, a layer of PrP and an outer accumulation of Ab. d Vessel wall with colocalisation of Ab and PrP (arrow). Bar=50 lm complementarily, and that each may act as a seed for the accumulation of the other. This mechanism could be evaluated in dual PrP-bAPP transgenic mice. A second possibility is that the accumulation of aberrant proteins (including Ab) due to diminished P-gp activity could overwhelm the protein-degrading enzymes of the ubiquitin-proteasomal system (UPS) and thereby facilitate the accumulation and conversion of PrP. The UPS plays a fundamental part in many basic cellular processes by degrading a wide range of specific cellular proteins, including mutated and misfolded proteins [10]. Dysfunction of the UPS contributes to the accumulation of proteins in neurodegenerative diseases, such as a-synuclein in PD [34], or Ab [29] and tau [31] in AD. PrP also is degraded via the UPS [35, 52]. Inhibition of the UPS, e.g., due to aging or drug treatment, causes an accumulation of normal PrPC in the cytoplasm, where it can be spontaneously converted into a PrPSc-like species because it is not promptly degraded by the UPS [30]. Interestingly, there are recent hints that P-gp interacts actively with the proteasome complex [4]. It cannot be excluded that, in CJD, there are additional mechanisms that damage the integrity of the BBB and, secondarily, reduce the expression of P-gp. However, since P-gp acts as a critical detoxifying system in the brain [42], we favor the hypothesis that the ageassociated decline in P-gp function elevates the levels of toxic proteins such as PrP in brain, thereby increasing the likelihood that they will accumulate to pathogenic levels via permissive templating [22]. Additionally, P-gp might play a part in the pathogenesis of neurodegenerative diseases by one or more indirect mechanisms. Diminished P-gp expression could cause a pronounced influx of exogenous, neurotoxic compounds, leading to the damage and loss of neurons that is believed to promote the development of some cases of idiopathic parkinsonism [16, 19]. What is more, P-gp could act as a neuroprotective factor by suppressing the activation of caspases [40, 41] involved in apoptosis. Similarities in the pathogenesis of aberrant protein deposits in CJD and AD have been suggested in the context of the concept of protein misfolding diseases, or proteopathies. Since these neurodegenerative disorders may be amenable to similar therapeutic principles [2, 48], selectively augmenting cerebral P-gp expression represents a novel therapeutic strategy to forestall the accumulation of insoluble proteins in the brain. P-gp activity can be modulated by a variety of substances such as verapamil or cyclosporin A (inhibition) [51], as well as rifampin or St. Johns wort (induction) [17, 23]. Because P-gp plays an important part in a variety of tissues, the challenge for drug discovery will be to identify an agent that selectively enhances P-gp function in the brain. Finally, it has been shown that the MDR1 gene, which codes for P-gp, is highly polymorphic [7, 24], and that P-gp expression can be influenced by these polymorphisms [24, 38]. Thus, it is conceivable that variations in the MDR1 gene might influence the risk of developing certain neurodegenerative proteopathies, including CJD, an issue that warrants further research. Conclusion The results of our study show that the cerebrovascular expression of the multifaceted transporter P-gp is downregulated in CJD. We propose that diminution of P-gp expression with age reduces the expulsion of toxic proteins by the BBB. The buildup of these proteins within cells overwhelms the protein degradation machinery, thereby further promoting the accumulation of aberrant proteins such as PrP. Our findings suggest that selectively augmenting cerebrovascular P-gp function could open new therapeutic pathways for the prevention and/ or treatment of prionoses and other proteopathic disorders of the central nervous system. Acknowledgments We thank S. Uffmann, A. Wolter, and C. Mueller for excellent technical assistance. References...snip...end http://www.springerlink.com/(nr3t22ep0fbzjxewejg2q3ra)/app/home/contribution.asp?referrer=parent&backto=issue,17,21;journal,1,511;linkingpublicationresults,1:100394,1 TSS
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