. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Nov;115(11):3285-90. PubMed.


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  1. This paper is a typically well-reasoned and very logical study from the group of David Holtzman. The authors show how P-glycoprotein (Pgp), which is involved in efflux transport of cytotoxic agents from tumor cells, is also involved in the transport of Aβ from brain into blood.

    The accumulation of insoluble material as plaques in gray matter of the brain in Alzheimer disease has been known for 100 years and this material was identified as amyloid-β 20 years ago. With the characterization of genetic defects in the amyloid precursor protein (APP) gene in relatively small numbers of cases of familial AD, the amyloid hypothesis was born, suggesting that overproduction of Aβ was a major factor in the pathogenesis of AD. However, there is little firm evidence that overproduction of Aβ occurs in the large number of cases of sporadic AD or in cognitively normal elderly individuals who also accumulate Aβ in the brain. Attention has turned, therefore, during the last few years towards failure of elimination of Aβ from the brain as a major factor in the pathogenesis of AD.

    Aβ is produced by neurons and other cells in the brain, and a number of different pathways for the elimination of Aβ from the brain have been identified. They include (a) active transport of Aβ from brain directly into the blood (Cirrito et al., 2005; Shibata et al., 2000); (b) proteolytic degradation of Aβ by enzymes in brain parenchyma (Iwata et al., 2002); and (c) removal of Aβ by bulk flow drainage with interstitial fluid (ISF) along capillary and artery walls (Weller et al., 1998).

    There are several exciting aspects of the present paper showing the involvement of P-glycoprotein (Pgp) in transport of Aβ out of the brain into the blood. The authors suggest that some polymorphisms in Pgp may restrict the elimination of Aβ, whereas others may enhance it. Perhaps of more immediate application to therapy of Alzheimer disease is the suggestion that some drugs, such as rifampin, are Pgp substrates and inducers. Because Pgp is located on the luminal surface of the endothelial cell, it is accessible to pharmacological influences as the drug is not required to cross the blood-brain barrier.

    So what of the future? Perhaps it is timely to look at the balance of the different known pathways for the elimination of Aβ from the human brain. Knowing how, why and to what extent each mechanism for elimination of Aβ fails in the elderly and in AD will guide the development of therapies to prevent AD and possibly to ameliorate established disease. There is some indication from studies in mice that active transport of Aβ from brain directly into the blood fails with age (Shibata et al., 2000), as does proteolytic degradation of Aβ by enzymes in brain parenchyma (Iwata et al., 2002), but less is known in this area in elderly humans. Removal of Aβ by bulk flow drainage with interstitial fluid along capillary and artery walls appears to fail with age in humans and results in deposition of Aβ in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA). Aging and stiffening of blood vessels with cerebrovascular disease may be a factor in the failure of elimination of Aβ by the perivascular route and the development of CAA (Weller et al., 2002; Weller and Nicoll, 2003; Schley et al., 2005). At the moment, the age changes that occur in human cerebral arteries are not built into mouse models used to study the elimination of Aβ.

    In devising suitable therapies for AD, can the absorption into the blood be enhanced in the elderly, as suggested by Cirrito et al.? Or can the elimination of Aβ along perivascular pathways be enhanced by suitable chaperone molecules? Removal of insoluble Aβ from brain parenchyma in AD does seem to occur following immunization against Aβ, both in mouse (Wilcock et al., 2004) and humans (Nicoll et al., 2003). At the same time, the severity of CAA increases following treatment (Wilcock et al., 2004), possibly because the soluble Aβ derived from amyloid plaques overloads perivascular drainage pathways.

    Many questions remain unanswered. For example: What is the relationship between the extracellular accumulation of Aβ in the brain in Alzheimer disease and the intracellular accumulation of tau protein and ubiquitin as neurofibrillary tangles (NFT)? Does the deposition of Aβ induce the formation of NFTs, as is suggested by some transgenic mouse models, or are they independent aging processes? Another question revolves around what exactly interferes with neuronal function in Alzheimer disease. Is it the insoluble plaques of Aβ or the NFTs, or is it the high levels of soluble Aβ in the interstitial fluid of the brain?

    One final point to consider is whether Aβ is actually the main toxic influence on neurons or whether its main role in AD is to block the extracellular spaces in brain parenchyma and the drainage pathways in vessel walls so that there is failure of elimination of a wide variety of metabolites in the interstitial fluid. Such failure of elimination of solutes and ions may significantly alter the composition of the extracellular fluid and the extracellular environment of neurons in the brain, and this may be a factor that induces neuronal dysfunction.

    Whatever the answers to the questions posed above, it does seem that a coordinated effort is required to understand how the various mechanisms of elimination of Aβ from the brain are balanced, why they appear to collectively fail in AD, and how elimination of Aβ can be most suitably enhanced for the prevention and treatment of this disease.

    View all comments by Roy Weller
  2. A recurring theme in the pathogenesis of diverse degenerative disorders is the accumulation of certain proteins in cells and tissues. Although many details remain to be ironed out, the pathogenic importance of cerebral Aβ accumulation in Alzheimer disease is now beyond reasonable dispute. Simply increasing the concentration of aggregation-prone proteins such as Aβ raises the odds that they will multimerize and deposit, as is demonstrated by various disease states and transgenic models. Thus, the more we know about how proteopathic proteins are made, transported, and dismantled, the better the chances that we can manipulate these processes for the benefit of patients.

    Aβ production and degradation have received the lion's share of attention in AD, and many of the cellular and molecular players in these processes have been identified. Less consideration has been given to the transport of the peptide, despite burgeoning evidence that it can be actively conveyed across cell membranes. Low-density lipoprotein receptor-related protein (LRP1) is one such Aβ-efflux transporter, and now Cirrito, Holtzman, and colleagues furnish compelling evidence that P-glycoprotein (Pgp) is another. Their experiments demonstrate that pharmacologic or genetic diminution of Pgp function decreases transport and increases the amount of Aβ in vivo, and that crossing Pgp-null mice with APP-transgenic mice results in an augmentation of age-associated cerebral Aβ deposition.

    Pgp is a promiscuous transporter that regulates the levels of xenobiotics and other substances in tissues that have a barrier and/or excretory role, such as intestine, kidney, liver, and (in the brain) the blood-brain barrier. Aβ was found to be a substrate for Pgp by Lam and colleagues, and Aβ deposition subsequently was noted to be increased in the brains of elderly humans who had reduced endothelial Pgp immunoreactivity (Vogelgesang et al., 2002; Vogelgesang et al., 2004). Because it can be induced or inhibited by various agents, Pgp presents an interesting and accessible target for regulating Aβ levels in brain. Ideally, of course, enhancement of Pgp activity should be selective for brain endothelial cells, and even if this tall order can be filled, the (theoretically) possible side effects of upregulating such a vital molecular ferry are an issue. On the other hand, the apparent benignity of existing upregulators suggests that Pgp could be a reasonably safe target, at least under most circumstances. I hope that the Cirrito study will stimulate further work in this arena. Finally, it is worth noting that, in addition to genetic and pharmacologic influences on Pgp function, the amount of the transporter in brain vessels appears to diminish with age (Vogelgesang et al., 2004), suggesting one potential means by which senescence increases the risk of idiopathic AD.

    View all comments by Lary Walker
  3. P-glycoprotein (Pgp) is a multifaceted protein that functions as an efflux pump of a variety of endogenous and exogenous compounds in different systemic organs. It is also well recognized in endothelial cells of the brain capillaries, thus playing an important role in the integrity of the blood-brain barrier (BBB). Since the accumulation of insoluble beta amyloid (Aβ) in the brains of patients with Alzheimer disease is thought to be, at least in part, due to insufficient clearance at the BBB, many efforts have been made to find the mechanisms by which Aβ is transported out of the brain. In addition to Pgp, other potential transport proteins such as LRP have been investigated by several research groups.

    On the basis of the results of Lam et al. (2001), we examined the relationship between Pgp expression and the amount of Aβ deposition in the brains of 243 non-demented elderly people, and found an inverse correlation between vascular Pgp and the quantity of Aβ-positive plaques, suggesting that Pgp might indeed play an important role in the pathogenesis of AD (Vogelgesang et al., 2002). In a subsequent study of the correlation between Pgp expression and cerebral amyloid angiopathy (CAA), we found an age-dependent decrease of Pgp expression in cases without CAA and an upregulation of endothelial Pgp in cases with CAA. Pgp and vascular Aβ were never colocalized, and the upregulation of Pgp was detected only in vessels that were not involved in the deposition of Aβ (Vogelgesang et al., 2004).

    In a series of elegant experiments, Cirrito et al. now have provided the strongest evidence to date that Pgp acts as a transporter for Aβ in the living brain, and that the activity of this transporter can minimize the accumulation of the peptide into amyloid lesions in the brains of transgenic mice. Since the expression of Pgp can be modulated by a range of pharmacological substances, these findings support efforts to develop therapeutic strategies directed toward the regulation of Aβ-transport to prevent Aβ accumulation, and thus, the development of AD. Because Pgp expels some therapeutic agents from target tissues, such as tumors or seizure-prone regions in medically intractable epilepsy, most efforts have been made to find substances that inhibit Pgp. In contrast, the goal of the treatment of AD must be the development of Pgp inducers. Such treatment will need to take into account each patient's global medication requirements, since Pgp inducers can reduce the efficacy of some other agents by promoting their removal.

    A second point that makes the Pgp story intriguing is that Pgp expression is believed to be influenced by polymorphisms in the MDR1 gene that encodes Pgp. It has been shown that the MDR1 gene is highly polymorphic. An alteration of transport function could be demonstrated for a C3435T single nucleotide polymorphism in the intestine, where the T allele was found to be associated with decreased Pgp levels, whereas the C allele yielded increased Pgp expression. In our cohort of non-demented elderly cases, we investigated several polymorphisms of the MDR1 gene, but we have not yet found a significant association between Pgp expression and the C3435T polymorphism (Vogelgesang et al., 2002).

    As nicely demonstrated by Cirrito and colleagues, it is now evident that Pgp plays an important role in the clearance of Aβ from brain, and hence may be involved in the development of AD as well as CAA. We hope that larger future efforts will be made to determine the role of Pgp in the pathogenesis of AD, to find possible risk factors for AD, and to develop new therapeutic strategies in the treatment of AD.

    View all comments by Silke Vogelgesang
  4. This study by the Holtzman lab is most interesting. I had proposed that inhibition of P-glycoprotein together with Gleevec may be a useful therapy in AD. The study I'd referenced in my poster found that levels of Gleevec in the brain were higher in mdr1a/b (/) knockout mice. Perhaps if P-glycoprotein is already reduced in AD, then Gleevec may be expected to cross the BBB in greater concentration and may be, in fact, a therapeutic option on its own.

    References: Gleevec for Alzheimer's?

    View all comments by Mary Reid