Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood–Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease
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UNLABELLED: Studies in animals and postmortem human brain tissue support a role for P-glycoprotein in clearance of cerebral β-amyloid across the blood-brain barrier (BBB). We tested the hypothesis that BBB P-glycoprotein activity is diminished in Alzheimer disease (AD) by accounting for an AD-related reduction in regional cerebral blood flow (rCBF). METHODS: We compared P-glycoprotein activity in mild-AD patients (n = 9) and cognitively normal, age-matched controls (n = 9) using PET with a labeled P-glycoprotein substrate, (11)C-verapamil, and (15)O-water to measure rCBF. BBB P-glycoprotein activity was expressed as the (11)C-verapamil radioactivity extraction ratio ((11)C-verapamil brain distributional clearance, K1/rCBF). RESULTS: Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects. CONCLUSION: BBB P-glycoprotein 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-glycoprotein activity and suggests that impaired P-glycoprotein activity may contribute to cerebral β-amyloid accumulation in AD. P-glycoprotein induction or activation to increase cerebral β-amyloid clearance could constitute a novel preventive or therapeutic strategy for AD.
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Studies using [11C]verapamil, an ABCB1 (P-gp) ligand and PET, have shown increased uptake of verapamil in certain brain regions in individuals with early AD.
“Studies using [ 11 C]verapamil, an ABCB1 (P-gp) ligand and PET, have shown increased uptake of verapamil in certain brain regions in individuals with early AD, suggesting diminished ABCB1-mediated active efflux of xenobiotics and drugs at the BBB (33, 142), and possibly faulty A 𝛃 BBB clearance based on experimental studies (115, 400, 632).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [142]
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- Authors
- Deo, A. K., Borson, S., Link, J. M., Domino, K., Eary, J. F., Ke, B., Richards, T. L., Mankoff, D. A., Minoshima, S., O’Sullivan, F., Eyal, S., Hsiao, P., Maravilla, K., & Unadkat, J. D.
- Affiliations
- University of Washington (US)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2014-05-19
- Volume
- 55
- Issue
- 7
- Pages
- 1106-1111
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC4691246
- OpenAlex
- W2130945756
- Cited by
- 193
- References
- 43
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 8 · 2023: 28 · 2022: 17 · 2021: 16 · 2020: 25 · 2019: 16 · 2018: 17 · 2017: 17 · 2016: 13 · 2015: 10 · 2014: 3
- FWCI
- 6.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Washington
- National Institutes of Health (TL1TR000422, UL1TR002319)
- National Institute on Aging (AG 031485, R33AG031485)
- National Center for Research Resources (TL1RR025016)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- P-glycoprotein, blood-brain barrier, Alzheimer's disease, amyloid-beta clearance, regional cerebral blood flow, [11C]verapamil, amyloid PET, hippocampus, temporoparietal cortex, frontal cortex, posterior cingulate cortex
- MeSH terms
- Adult, Aged, Alzheimer Disease, Blood-Brain Barrier, Carbon Radioisotopes, Cerebrovascular Circulation, Female, Humans, Male, Middle Aged, Oxygen Radioisotopes, Verapamil, Water, Case-Control Studies, Amyloid beta-Peptides, ATP Binding Cassette Transporter, Subfamily B, Member 1, Positron-Emission Tomography, Young Adult
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