Impairments in Brain-to-Blood Transport of Amyloid-β and Reabsorption of Cerebrospinal Fluid in an Animal Model of Alzheimer's Disease are Reversed by Antisense Directed Against Amyloid-β Protein Precursor
Impairments in Brain-to-Blood Transport of Amyloid-β and Reabsorption of Cerebrospinal Fluid in an Animal Model of Alzheimer's Disease are Reversed by Antisense Directed Against Amyloid-β Protein Precursor
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DOI：
10.3233/jad-2010-100021
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Morley, John E.
中科院分区：
文献类型：
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作者：
Banks, William A.;Kumar, Vijaya B.;Morley, John E.
血脑屏障（BBB）通过将β转运出脑（外排）和脑脊液（CSF）重吸收进入血流（大流量）来影响β淀粉样蛋白（A β）的脑水平。在阿尔茨海默病（AD）和正常衰老中，未知因素损害衰老和AD中的A β外排和大流量。这些损伤被认为是大脑A β负荷增加的机制。A - β外排损伤发生在AD的动物模型中，包括年老的SAMP8小鼠。在这里，我们发现SAMP8小鼠的脑脊液重吸收也减少了约50% （p < 0.05）。然后，我们确定了一种针对淀粉样蛋白前体（A β PP） A β区域的反义蛋白是否能够逆转这些损伤，这种反义蛋白先前显示可以降低大脑中A β PP的水平，并逆转SAMP8小鼠的认知障碍。我们发现反义蛋白恢复了脑脊液的重吸收，使A β的流出速率增加了一倍以上，并恢复了A β的可饱和流出。这些结果表明，A β - PP/A β本身导致了A β的大流量和饱和外排的损伤，而A β - PP/A β水平的降低可以恢复血脑屏障的正常功能。
The blood-brain barrier (BBB) influences brain levels of amyloid-beta (A beta) by transporting A beta out of the brain (efflux) and by the reabsorption of cerebrospinal fluid (CSF) into the blood stream (bulk flow). In Alzheimer's disease (AD) and normal aging, unknown factors impair A beta efflux and bulk flow in aging and in AD. These impairments have been proposed as mechanisms by which the A beta burden in brain can increase. Impairment in A beta efflux occurs in animal models of AD, including the aged SAMP8 mouse. Here, we show that CSF reabsorption is also reduced by about 50% in SAMP8 mice (p < 0.05). We then determined whether an antisense directed at the A beta region of the amyloid-beta protein precursor (A beta PP) and previously shown to decrease brain levels of A beta PP and to reverse the cognitive impairments of the SAMP8 mouse was able to reverse these impairments. We found that the antisense restored both the CSF reabsorption, more than doubling the rate of efflux, and the saturable efflux of A beta. These findings suggest that A beta PP/A beta itself contributes to the impairments in bulk flow and saturable efflux of A beta and that reduction of A beta PP/A beta levels can restore normal function of the BBB.