Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood–Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease

Abstract

Animal and histopathological studies of human brain support a role for P-glycoprotein (P-gp) in clearance of cerebral β-amyloid (Aβ) across the blood brain barrier (BBB). We tested the hypothesis that BBB P-gp activity is diminished in Alzheimer’s disease (AD) by accounting for AD-related reduction in regional cerebral blood flow (rCBF). Methods We compared P-gp activity in mild AD patients (n=9) and cognitively normal, age-matched controls (n=9) using positron emission tomography (PET) with a labeled P-gp substrate, [11C]-verapamil, and [15O]-water to measure rCBF. BBB P-gp activity was expressed as the [11C]-verapamil radioactivity extraction ratio (ER={[11C]-verapamil brain distributional clearance, K1}/rCBF). Results Compared to controls, BBB P-gp activity was significantly lower in the parietotemporal, frontal, posterior cingulate cortices and hippocampus of mild AD subjects. Conclusion BBB P-gp activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-gp activity and suggests that impaired P-gp activity may contribute to cerebral Aβ accumulation in AD. P-gp induction/activation to increase cerebral Aβ clearance could constitute a novel preventive or therapeutic strategy for AD.

Role of (Drug) Transporters in Imaging in Health and Disease

“…Similarly, as previously demonstrated by us and others (Sasongko et al, 2005;Hsiao et al, 2008;Eyal et al, 2009Eyal et al, , 2010Muzi et al, 2009;Bauer et al, 2012;Mullauer et al, 2012;Bankstahl et al, 2013;Ke et al, 2013;Deo et al, 2014), when a drug is effluxed out of the brain, its concentration in the brain can be much lower than that in the plasma. This disconnect between tissue and plasma drug concentration will be modulated in the presence of a drug-drug interaction (DDI).…”

“…Such data are best obtained using noninvasive imaging methods (such as PET imaging) to determine drug transport concentrations in various tissues (e.g., brain, fetus, and liver). Such data are available from our laboratory (Hsiao et al, 2008;Eyal et al, 2009Eyal et al, , 2010Muzi et al, 2009;Ke et al, 2013;Deo et al, 2014;He et al, 2014) and others. Therefore, the accuracy of the above proposed IVIVE method can now be tested.…”

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

“…Furthermore, the same authors also observed a negative correlation between capillary Pgp expression and neurofibrillary tangles in AD brains. Importantly, the activity of this BBB transporter was also reduced in several brain regions, including the hippocampus, of mild AD patients [122]. The mechanism underlying Pgp action in limiting Aβ accumulation in the brain is still under debate, with studies pointing to the clearance of Aβ from the abluminal to the luminal side of the membrane, while others indicate that the strategic position of the transporter at the luminal side of the BBB limits Aβ entry into the brain [123].…”

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

“…The advantage of the statistical mapping is that no assumption is made regarding the relevant regions and that it can be used to analyze the entire tissue observed in the image (e.g., brain) (28). Thus, it can detect changes outside a priori specified regions and is therefore useful for identification of regional changes in transporter activity, e.g., in epilepsy (39) and Alzheimer's disease (40,41), and potentially also in tumors and their metastases.…”