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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.
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Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.

机译：在小鼠中枢神经系统中清除人类阿尔茨海默氏症淀粉样β肽和载脂蛋白E和J的转运途径。

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摘要

Amyloid beta-peptide (Abeta) clearance from the central nervous system (CNS) maintains its low levels in brain. In Alzheimer's disease, Abeta accumulates in brain possibly because of its faulty CNS clearance and a deficient efflux across the blood-brain barrier (BBB). By using human-specific enzyme-linked immunosorbent assays, we measured a rapid 30 mins efflux at the BBB and transport via the interstitial fluid (ISF) bulk flow of human-unlabeled Abeta and of Abeta transport proteins, apolipoprotein E (apoE) and apoJ in mice. We show (i) Abeta40 is cleared rapidly across the BBB via low-density lipoprotein receptor-related protein (LRP)1 at a rate of 0.21 pmol/min g ISF or 6-fold faster than via the ISF flow; (ii) Abeta42 is removed across the BBB at a rate 1.9-fold slower compared with Abeta40; (iii) apoE, lipid-poor isoform 3, is cleared slowly via the ISF flow and across the BBB (0.03-0.04 pmol/min g ISF), and after lipidation its transport at the BBB becomes barely detectable within 30 mins; (iv) apoJ is eliminated rapidly across the BBB (0.16 pmol/min g ISF) via LRP2. Clearance rates of unlabeled and corresponding 125I-labeled Abeta and apolipoproteins were almost identical, but could not be measured at low physiologic levels by mass spectrometry. Amyloid beta-peptide 40 binding to apoE3 reduced its efflux rate at the BBB by 5.7-fold, whereas Abeta42 binding to apoJ enhanced Abeta42 BBB clearance rate by 83%. Thus, Abeta, apoE, and apoJ are cleared from brain by different transport pathways, and apoE and apoJ may critically modify Abeta clearance at the BBB.
机译：淀粉样蛋白β肽（Abeta）从中枢神经系统（CNS）的清除维持其在大脑中的低水平。在阿尔茨海默氏病中，Abeta可能由于其错误的中枢神经系统清除能力和血脑屏障（BBB）流出不足而在大脑中蓄积。通过使用人类特异性酶联免疫吸附试验，我们在BBB处测量了30分钟的快速流出，并通过人类未标记的Abeta和Abeta转运蛋白，载脂蛋白E（apoE）和apoJ的间质液（ISF）大流量转运在小鼠中。我们显示（i）Abeta40通过低密度脂蛋白受体相关蛋白（LRP）1以0.21 pmol / min g ISF的速度快速通过BBB清除，或比通过ISF流动快6倍; （ii）与Abeta40相比，Abeta42在整个血脑屏障中的去除速度要慢1.9倍; （iii）通过ISF流并穿过BBB（0.03-0.04 pmol / min g ISF）缓慢清除apoE，即贫脂同工型3，并且在脂化后30分钟内几乎无法检测到其在BBB上的转运; （iv）通过LRP2在整个BBB中迅速消除apoJ（0.16 pmol / min g ISF）。未标记的和相应的125I标记的Abeta和载脂蛋白的清除率几乎相同，但无法通过质谱法在低生理水平下测量。与apoE3结合的淀粉样β肽40将其在BBB的外排率降低了5.7倍，而与apoJ结合的Abeta42将Abeta42 BBB的清除率提高了83％。因此，Abeta，apoE和apoJ通过不同的运输途径从大脑清除，并且apoE和apoJ可能会严重修饰BBB处的Abeta清除率。

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