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P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model
Open accessAbstract
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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“Before injection of tracer molecules, animals recovered for 4 to 6 hours, a time point that precedes the start of the substantial inflammatory process, as assessed by histological analysis of tissue (negative staining for reactive astrocytes [GFAP] and reactive microglia [antiphosphotyrosine]), but allows partial BBB repair for large molecules, as reported previously (15,61).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [61]
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“ABCB1 contributes to Alzheimer's A 𝛃 toxin clearance from brain-to-blood (115, 632).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [115]
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“but it is now clear that ABCB1 is also involved in A peptide transport across the BBB.”
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“Whereas some studies have reported a role for ABCB1 in A peptide elimination from the brain [37,67]”
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Metadata
- 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
- Published
- 2005-11-01
- Volume
- 115
- Issue
- 11
- Pages
- 3285-3290
- ISSN
- 0021-9738 (ISSN-L)
- 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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