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

Anna L. Bartels; Rudie Kortekaas; Joost Bart; Antoon T. M. Willemsen; Onno L. de Klerk; Jeroen J. de Vries; Joost C. H. van Oostrom; Klaus L. Leenders

doi:10.1016/j.neurobiolaging.2008.02.002

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

Anna L. Bartels^*, Rudie Kortekaas, Joost Bart, Antoon T. M. Willemsen, Onno L. de Klerk, Jeroen J. de Vries, Joost C. H. van Oostrom, Klaus L. Leenders

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

116 Citations (Scopus)

Abstract

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. (C) 2008 Elsevier Inc. All rights reserved.

Original language	English
Pages (from-to)	1818-1824
Number of pages	7
Journal	Neurobiology of Aging
Volume	30
Issue number	11
DOIs	https://doi.org/10.1016/j.neurobiolaging.2008.02.002
Publication status	Published - Nov-2009

Keywords

Aging
P-glycoprotein
PET
[(11)C]-verapamil
Blood-brain barrier
Neurodegeneration
Alzheimer
Parkinson
White matter
POSITRON-EMISSION-TOMOGRAPHY
MULTIDRUG-RESISTANCE GENE
PARKINSONS-DISEASE
IN-VIVO
AMYLOID-BETA
ALZHEIMERS-DISEASE
ABC TRANSPORTERS
POTENTIAL ROLE
MOUSE-BRAIN
MDR1 GENE

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10.1016/j.neurobiolaging.2008.02.002

Cite this

Bartels, A. L., Kortekaas, R., Bart, J., Willemsen, A. T. M., de Klerk, O. L., de Vries, J. J., van Oostrom, J. C. H., & Leenders, K. L. (2009). Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration. Neurobiology of Aging, 30(11), 1818-1824. https://doi.org/10.1016/j.neurobiolaging.2008.02.002

Bartels, Anna L. ; Kortekaas, Rudie ; Bart, Joost ; Willemsen, Antoon T. M. ; de Klerk, Onno L. ; de Vries, Jeroen J. ; van Oostrom, Joost C. H. ; Leenders, Klaus L. / Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging : A possible role in progressive neurodegeneration. In: Neurobiology of Aging. 2009 ; Vol. 30, No. 11. pp. 1818-1824.

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abstract = "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. (C) 2008 Elsevier Inc. All rights reserved.",

keywords = "Aging, P-glycoprotein, PET, [(11)C]-verapamil, Blood-brain barrier, Neurodegeneration, Alzheimer, Parkinson, White matter, POSITRON-EMISSION-TOMOGRAPHY, MULTIDRUG-RESISTANCE GENE, PARKINSONS-DISEASE, IN-VIVO, AMYLOID-BETA, ALZHEIMERS-DISEASE, ABC TRANSPORTERS, POTENTIAL ROLE, MOUSE-BRAIN, MDR1 GENE",

author = "Bartels, {Anna L.} and Rudie Kortekaas and Joost Bart and Willemsen, {Antoon T. M.} and {de Klerk}, {Onno L.} and {de Vries}, {Jeroen J.} and {van Oostrom}, {Joost C. H.} and Leenders, {Klaus L.}",

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language = "English",

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pages = "1818--1824",

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Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging : A possible role in progressive neurodegeneration. / Bartels, Anna L.; Kortekaas, Rudie; Bart, Joost ; Willemsen, Antoon T. M.; de Klerk, Onno L.; de Vries, Jeroen J.; van Oostrom, Joost C. H.; Leenders, Klaus L.

In: Neurobiology of Aging, Vol. 30, No. 11, 11.2009, p. 1818-1824.

Research output: Contribution to journal › Article › Academic › peer-review

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AU - Bartels, Anna L.

AU - Kortekaas, Rudie

AU - Bart, Joost

AU - Willemsen, Antoon T. M.

AU - de Klerk, Onno L.

AU - de Vries, Jeroen J.

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AB - 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. (C) 2008 Elsevier Inc. All rights reserved.

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KW - White matter

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KW - PARKINSONS-DISEASE

KW - IN-VIVO

KW - AMYLOID-BETA

KW - ALZHEIMERS-DISEASE

KW - ABC TRANSPORTERS

KW - POTENTIAL ROLE

KW - MOUSE-BRAIN

KW - MDR1 GENE

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DO - 10.1016/j.neurobiolaging.2008.02.002

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JO - Neurobiology of Aging

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