Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

  • van Assema D
  • Lubberink M
  • Bauer M
 et al. 
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Abstract

A major pathological hallmark of Alzheimer's disease is accumulation
of amyloid-β in senile plaques in the brain. Evidence is accumulating
that decreased clearance of amyloid-β from the brain may lead to
these elevated amyloid-β levels. One of the clearance pathways of
amyloid-β is transport across the blood-brain barrier via efflux
transporters. P-glycoprotein, an efflux pump highly expressed at
the endothelial cells of the blood-brain barrier, has been shown
to transport amyloid-β. P-glycoprotein function can be assessed
in vivo using (R)-[(11)C]verapamil and positron emission tomography.
The aim of this study was to assess blood-brain barrier P-glycoprotein
function in patients with Alzheimer's disease compared with age-matched
healthy controls using (R)-[(11)C]verapamil and positron emission
tomography. In 13 patients with Alzheimer's disease (age 65 ± 7
years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil
binding potential values were increased significantly (P = 0.001)
compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental
State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding
potential values were 2.18 ± 0.25 for patients with Alzheimer's
disease and 1.77 ± 0.41 for healthy controls. In patients with
Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential
values were found for frontal, parietal, temporal and occipital cortices,
and posterior and anterior cingulate. No significant differences
between groups were found for medial temporal lobe and cerebellum.
These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's
disease, similar to alterations seen in studies where P-glycoprotein
is blocked by a pharmacological agent. As such, these data indicate
that P-glycoprotein function is decreased in patients with Alzheimer's
disease. This is the first direct evidence that the P-glycoprotein
transporter at the blood-brain barrier is compromised in sporadic
Alzheimer's disease and suggests that decreased P-glycoprotein function
may be involved in the pathogenesis of Alzheimer's disease.

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Authors

  • Danielle M E van Assema

  • Mark Lubberink

  • Martin Bauer

  • Wiesje M van der Flier

  • Robert C Schuit

  • Albert D Windhorst

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