P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model
P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model
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DOI：
10.1172/jci25247
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Cirrito, JR;Deane, R;Holtzman, DM
淀粉样β蛋白(Aβ)在脑细胞外空间的积聚是阿尔茨海默病(AD)的一个特征。在散发性、晚发型AD中，几乎没有证据表明A产生增加，这表明从大脑中清除减少可能导致Aβ水平升高和斑块形成。Aβ通过血脑屏障(BBB)的外流运输有助于Aβ从脑中的清除。β-糖蛋白(PGP)高表达于脑毛细血管内皮细胞的管腔表面，参与血脑屏障的形成。在Pgp缺失的小鼠中，我们发现显微注射到中枢神经系统的[I-125]A beta(40)和[I-125]A beta(42)的清除速度是WT小鼠的一半。当淀粉样前体蛋白转基因(APP-转基因)小鼠被给予PGP抑制剂时，脑间质液中的Aβ水平在治疗后几个小时内显著增加。此外，与APP转基因PGP WT小鼠相比，APP转基因Pgp缺失小鼠的脑Aβ水平和Aβ沉积增加。这些数据建立了体内Pgp和Aβ代谢之间的直接联系，并表明BBB处的Pgp活性可能影响发生AD的风险，并提供一个新的诊断和治疗靶点。
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.