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

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.

Hybrid Imaging: Instrumentation and Data Processing

“…An IF can be employed together with a physiological model in order to calculate physiological parameters, such as metabolic rate of glucose (umol/100 g/min) or blood flow (ml/100 g/min) [250]. The creation of such parametric images can be divided into [208], (E) Anazodo et al [209], (F) Izquierdo-Garcia et al [210], (G) Burgos et al [211], (H) Merida et al [212]; MLAA-based methods: (I) Benoit et al [213]; Segmentation-based methods: (J) Cabello et al [214], (K) Juttukonda et al [215], (L) Ladefoged et al [216].…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…Evidence supporting this role for Pgp includes: (1) observations of Pgp-dependent efflux of Ab in vitro, 59,60 (2) an inverse correlation of Ab deposition and microvascular Pgp expression in human brain tissue, 61 (3) decreased Ab efflux and enhanced Ab deposition in mice that lack Pgp, 62 (4) impaired microvascular Pgp function in a transgenic AD mouse model that is restored by pharmacologic intervention shows corresponding improvement in Ab efflux and reduced Ab deposition, 62,63 and (5) showing Pgp dysfunction in human AD using clinical PET imaging studies. 64 Because of its luminal location, 65 it has been proposed that Pgp facilitates the extrusion of Ab from the endothelial cell into the bloodstream after Ab has been internalized from brain interstitial fluid (ISF) by LRP-1. 63 However, our group has found that under inflammatory conditions, antioxidant treatment that preserves LRP-1 but not Pgp function also preserves Ab efflux.…”

The ABCB1 Transporter in Alzheimer’s Disease

“…Van Assema et al [10] assessed the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on BBB P-gp function in healthy subjects and patients with AD. In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T.…”

“…ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the BBB and brain parenchyma, affect Aβ transport (flux) across the BBB contributing to the pathogenesis of Alzheimer's disease (AD) [5][6][7][8][9][10][11][12]. One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters.…”

“…One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation [5][6][7][8][9][10][11][12]. Deficiency of either of the two major efflux pumps, ABCB1 and ABCG2, involved in Aβ trafficking across the BBB, results in increased accumulation of peripherallyinjected Aβ in the brain [13].…”