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

Accumulation of amyloid-beta (A beta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased A production, suggesting that decreased elimination from the brain may contribute to elevated levels of A beta and plaque formation. Efflux transport of A beta across the blood-brain barrier (BBB) contributes to A beta removal from the brain. beta-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-125]A beta(40) and [I-125]A beta(42) 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, A beta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain A beta and enhanced A beta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and A beta 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.