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From: TSS ()
Subject: Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt-Jakob disease
Date: April 25, 2006 at 10:54 am PST

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.


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.


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.



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