Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration

Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Neurobiology of aging (Impact Factor: 5.01). 04/2008; 30(11):1818-24. DOI: 10.1016/j.neurobiolaging.2008.02.002
Source: PubMed


Cerebrovascular P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of neurodegenerative pathology with aging. We hypothesised a regionally reduced BBB P-gp function in older healthy subjects. We studied cerebrovascular P-gp function using [(11)C]-verapamil positron emission tomography (PET) in seventeen healthy volunteers with age 18-86. Logan analysis was used to calculate the distribution volume (DV) of [(11)C]-verapamil in the brain. Statistical Parametric Mapping was used to study specific regional differences between the older compared with the younger adults. Older subjects showed significantly decreased P-gp function in internal capsule and corona radiata white matter and in orbitofrontal regions. Decreased BBB P-gp function in those regions could thus explain part of the vulnerability of the aging brain to white matter degeneration. Moreover, decreased BBB P-gp function with aging could be a mechanism by which age acts as the main risk factor for the development of neurodegenerative disease.

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Available from: Anna L Bartels, Oct 06, 2015
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    • "Does an impairment of ABC transporters in distinct brain regions lead to a disturbed detoxification of these areas, which results in the development of toxic peptide aggregates (Bartels et al., 2008a; Pahnke et al., 2009a)? Mawuenyega and colleagues proved an impairment of the detoxification mechanisms/or processes by measuring both the production of Ab40/Ab42 and the clearance rates from the CNS of elderly patients suffering from AD and age-matched controls. "
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    ABSTRACT: Ageing is the main risk factor for the development of dementing neurodegenerative diseases (NDs) and it is accompanied by the accumulation of variations in mitochondrial DNA. The resulting tissue-specific alterations in ATP production and availability cause deteriorations of cerebral clearance mechanisms that are important for the removal of toxic peptides and its aggregates. ABC transporters were shown to be the most important exporter superfamily for toxic peptides, e.g. β-amyloid and α-synuclein. Their activity is highly dependent on the availability of ATP and forms a directed energy-exporter network, linking decreased mitochondrial function with highly impaired ABC transporter activity and disease progression. In this paper, we describe a network based on interactions between ageing, energy metabolism, regeneration, accumulation of toxic peptides and the development of proteopathies of the brain with a focus on Alzheimer's disease (AD). Additionally, we provide new experimental evidence for interactions within this network in regenerative processes in AD.
    Mechanisms of ageing and development 09/2013; 134(10). DOI:10.1016/j.mad.2013.08.007 · 3.40 Impact Factor
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    • "Of note, the results showing a decrease in P-gp functionality relative to PD progression do not confirm whether or not this is a consequence of the antiparkinsonian therapy. Thus, further studies observed that during aging, low P-gp activity is naturally found in elderly healthy volunteers in comparison with young healthy subjects [185] [186], which suggests a possible correlation between an impaired P-gp functionality and the onset of brain diseases. Despite these large number of studies using 11 C-verapamil, the presence of polar radio-metabolites limit its use [187] [188]. "
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    08/2013; 3(3). DOI:10.3233/JPD-130207
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    • "It is noteworthy, that ABCB1 expression in brain endothelial cells decreases with physiological aging, as shown in long-lived B-N/F rats, which interestingly caused brain accumulation of exogenously administered Aβ (Silverberg et al., 2010). In human brain, ABCB1 expression has been reported to decrease in elderly subjects (Bartels et al., 2009). This observation is highly important, because the decreased expression of ABCB1 impeded NVU's capacity in acting as a gatekeeper for the brain, allowing endogenous and exogenous toxins, like Aβ, to accumulate in the brain, thus inducing neuronal dysfunction. "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects elderly persons, evolving with age to reach severe cognitive impairment. Amyloid deposits and neurofibrillary tangles constitute the main pathological hallmarks of AD. Amyloid deposits are initiated by the excessive production and accumulation of beta-amyloid (Aβ) peptides in the brain. The dysfunction of the Neurovascular Unit (NVU) has been proposed to be causative in AD development, due to an impaired clearance of Aβ from the brain. Cells forming the NVU express several Adenosine Triphosphate ATP-Binding Cassette (ABC) transporters, among which ABCB1 and ABCA1 play an important role in Aβ processing. The drug transporter ABCB1 directly transports Aβ from the brain into the blood circulation, whereas the cholesterol transporter ABCA1 neutralizes Aβ aggregation capacity in an Apolipoprotein E (ApoE)-dependent manner, facilitating Aβ subsequent elimination from the brain. In the present minireview, we will summarize the contribution of ABCB1, and ABCA1 at the NVU in Aβ clearance. Moreover, we will outline and discuss the possible collaboration of ABCB1, and ABCA1 at the NVU in mediating an efficient clearance of Aβ from the brain.
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