Cited by 662Alzheimer's disease research and treatmentsDrug Transport and Resistance MechanismsBarrier Structure and Function Studies

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P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

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Cirrito, J. R.·2005·Journal of Clinical Investigation

DOI 10.1172/jci25247PMC PMC1257538

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Abstract

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.

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Authors: Cirrito, J. R.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Cirrito, J. R.
ORCID: Cirrito, J. R.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2005-11-01
Volume: 115
Issue: 11
Pages: 3285-3290
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci25247
PMC: PMC1257538
OpenAlex: W2163209521
Cited by: 660
References: 34
Citations by year: 2026: 21 · 2025: 24 · 2024: 29 · 2023: 36 · 2022: 31 · 2021: 30 · 2020: 37 · 2019: 31 · 2018: 30 · 2017: 35 · 2016: 43 · 2015: 40 · 2014: 41 · 2013: 44 · 2012: 26
FWCI: 12.44
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders: U.S. Department of Energy
National Institutes of Health (CA94056, AG13956)
National Institute on Aging (AG023316, R03AG023316, R01AG023084, AG23084, R01AG013956, R37AG023084, R37AG013956)
National Cancer Institute (P50 CA94056, P50CA094056)
National Institute of Allergy and Infectious Diseases (AI-13956)
National Institute of Neurological Disorders and Stroke (NS034467, R37NS034467, R01NS034467)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: P-glycoprotein, blood-brain barrier, amyloid-beta, Alzheimer's disease, APP transgenic mice, P-glycoprotein inhibitors, brain interstitial fluid, amyloid-beta clearance, brain microvascular endothelial cells, amyloid-beta deposition
MeSH terms: Alzheimer Disease, Animals, Blood-Brain Barrier, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Polymorphism, Genetic, Up-Regulation, Amyloid beta-Peptides, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Member 1, Mice

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P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

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