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P-glycoprotein Deficiency at the Blood-Brain Barrier Increases Amyloid-β Deposition in an Alzheimer Disease Mouse Model

Performed in collaboration with David Holtzman's Lab.
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.
Figure 1
Increased Aβ accumulation in APPsw, Pgp-null mice. (A,B) Brain sections from APPsw mice expressing or lacking Pgp were stained with an anti-Aβ antibody. Twelve-month-old APPsw, Pgp-null (mdr1a/b-/-) mice showed greater Aβ deposition within the hippocampus and cortex than their Pgp WT littermates. Scale bar: 250 µm. (C) As quantified by unbiased stereological techniques, Pgp-null mice exhibited a greater percentage of the hippocampus covered by Aβ immunoreactivity (% Aβ load) than Pgp WT mice; **P = 0.0041. The pattern of Aβ deposition within the hippocampus was similar in both genotypes. (D) Similar to the hippocampus, there was also a trend for greater Aβ immunoreactivity within the cortex of Pgp-null animals; P = 0.2788. Values are mean ± SEM; n = 11-16 per group.
References:	Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn, MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DH. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-w deposition in an Alzheimer's disease mouse model. J Clin Invest 2005; 115(11): 3285-90.	PubMed Link

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