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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2005-11, Vol.115 (11), p.3285-3290
Main Authors: Cirrito, John R, Deane, Rashid, Fagan, Anne M, Spinner, Michael L, Parsadanian, Maia, Finn, Mary Beth, Jiang, Hong, Prior, Julie L, Sagare, Abhay, Bales, Kelly R, Paul, Steven M, Zlokovic, Berislav V, Piwnica-Worms, David, Holtzman, David M
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Animals
ATP Binding Cassette Transporter, Subfamily B, Member 1 - deficiency
ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology
Blood-Brain Barrier - metabolism
Disease Models, Animal
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Polymorphism, Genetic
Up-Regulation - genetics
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI25247