转基因小鼠
血脑屏障
P-糖蛋白
转基因
淀粉样前体蛋白
体内
生物
内分泌学
淀粉样蛋白(真菌学)
细胞外
内科学
糖蛋白
阿尔茨海默病
化学
中枢神经系统
细胞生物学
医学
疾病
分子生物学
生物化学
基因
生物技术
抗生素
多重耐药
植物
作者
John R. Cirrito,Rashid Deane,Anne M. Fagan,Michael L. Spinner,Maia Parsadanian,Mary Beth Finn,Hong Jiang,Julie L. Prior,Abhay P. Sagare,Kelly R. Bales,Steven M. Paul,Berislav V. Zloković,David Piwnica‐Worms,David M. Holtzman
摘要
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 [ 125 I]Aβ 40 and [ 125 I]Aβ 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, 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.
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