P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model
John R. Cirrito, Rashid Deane, Anne M. Fagan, Michael L. Spinner, Maia Parsadanian, Mary Beth Finn, Hong Jiang, Julie L. Prior, Abhay Sagare, Kelly R. Bales, Steven M. Paul, Berislav V. Zlokovic, David Piwnica-Worms, David M. Holtzman
John R. Cirrito, Rashid Deane, Anne M. Fagan, Michael L. Spinner, Maia Parsadanian, Mary Beth Finn, Hong Jiang, Julie L. Prior, Abhay Sagare, Kelly R. Bales, Steven M. Paul, Berislav V. Zlokovic, David Piwnica-Worms, David M. Holtzman
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Research Article Neuroscience

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

Abstract

Accumulation of amyloid-β (Aβ) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Aβ production, suggesting that decreased elimination from the brain may contribute to elevated levels of Aβ and plaque formation. Efflux transport of Aβ across the blood-brain barrier (BBB) contributes to Aβ 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 [125I]Aβ40 and [125I]Aβ42 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, Aβ levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Aβ and enhanced Aβ deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Aβ 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.

Authors

John R. Cirrito, Rashid Deane, Anne M. Fagan, Michael L. Spinner, Maia Parsadanian, Mary Beth Finn, Hong Jiang, Julie L. Prior, Abhay Sagare, Kelly R. Bales, Steven M. Paul, Berislav V. Zlokovic, David Piwnica-Worms, David M. Holtzman

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Biodistribution of a Pgp substrate in APPsw, Pgp-null mice. Following ta...
Biodistribution of a Pgp substrate in APPsw, Pgp-null mice. Following tail vein bolus injection of 2 μCi [99mTc]Sestamibi, brain content of [99mTc]Sestamibi in 2- to 4-month-old WT and Pgp-null mice (on an FVB background), as well as APPsw mice expressing or lacking Pgp, was determined 5 minutes after injection. More tracer was retained in all Pgp-null mice (*P = 0.0043, FVB strain; **P = 0.0058, APPsw+/– strain), demonstrating, as expected, that Pgp normally hinders the entry of [99mTc]Sestamibi into the brain. Taken together, these finding suggest that Pgp expressed on the BBB behaves similarly in WT and APPsw mice. ID, injected dose.