Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.
Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.
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DOI：
10.3233/jad-2009-1074
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Banks WA
中科院分区：
文献类型：
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作者：
Jaeger LB;Dohgu S;Hwang MC;Farr SA;Murphy MP;Fleegal-DeMotta MA;Lynch JL;Robinson SM;Niehoff ML;Johnson SN;Kumar VB;Banks WA
清除能力降低是阿尔茨海默病(AD)患者脑内淀粉样蛋白(Aβ，Aβ)升高的主要原因。神经血管假说认为，低密度脂蛋白受体相关蛋白-1是A-β在血脑屏障的主要脑-血转运体，其清除能力的下降是由低密度脂蛋白受体相关蛋白-1受损引起的。由于LRP-1基因的缺失是一种致命的突变，我们通过开发针对LRP-1mRNA的硫代磷酸反义鸡尾酒来检验神经血管假说。我们发现，与随机反义相比，这些反义基因选择性地降低了LRP-1的表达，减少了Aβ42的血脑屏障清除，增加了Aβ42的脑水平，并损害了小鼠的学习和再认记忆。这些结果支持血脑屏障lrp-1功能障碍是脑内Aβ水平升高和AD发病的机制之一。
Decreased clearance is the main reason amyloid-β protein (Aβ) in increased in the brains of patients with Alzheimer’s disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Aβ at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Aβ42, increased brain levels of Aβ42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Aβ could increase and AD would be promoted.