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.

doi:10.1016/j.neurobiolaging.2008.02.002

« Previous Next »Neurobiology of Aging
Volume 30, Issue 11 , Pages 1818-1824, November 2009

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

Anna L. Bartels
- Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
- Corresponding author. Tel.: +31 50 3612433; fax: +31 50 3611707.
Rudie Kortekaas
- Department of Anatomy, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Joost Bart
- Department of Pathology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Antoon T.M. Willemsen
- Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Onno L. de Klerk
- Department of Psychiatry, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Jeroen J. de Vries
- Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Joost C.H. van Oostrom
- Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Klaus L. Leenders
- Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands

Received 6 September 2007; received in revised form 11 January 2008; accepted 5 February 2008. published online 25 March 2008.

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 [¹¹C]-verapamil positron emission tomography (PET) in seventeen healthy volunteers with age 18–86. Logan analysis was used to calculate the distribution volume (DV) of [¹¹C]-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.

Keywords: Aging, P-glycoprotein, PET, [¹¹C]-verapamil, Blood–brain barrier, Neurodegeneration, Alzheimer, Parkinson, White matter