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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease
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Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

机译：阻断载脂蛋白E /淀粉样蛋白β相互作用作为阿尔茨海默氏病的潜在治疗方法

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摘要

The amyloid-β (Aβ) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Aβ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Aft and apolipoprotein E (apoE) is an important factor implicated in both Aβ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Aβ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Aβ12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Aβ. Aβ12-28P binds with high affinity to apoE, preventing its binding to Aβ, but has no direct effect on Aβ aggregation. Aβ12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Aβ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Aβ in two AD transgenic mice models. The treatment did not affect the levels of soluble Aβ fraction or Aβ oligomers, indicating that inhibition of the apoE/Aβ interaction in vivo has a net effect of increasing Aβ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Aβ12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.
机译：阿尔茨海默氏病（AD）的淀粉样β（Aβ）级联假说认为，Aβ肽的积累构成了疾病早期发病机制中的关键事件。 Aft和载脂蛋白E（apoE）之间的直接结合是与Aβ清除及其在脑实质和脑膜脑血管壁沉积有关的重要因素，这是脑淀粉样血管病。为了测试体内阻断apoE /Aβ相互作用作为AD药物治疗的潜在新治疗靶标的作用，我们开发了Aβ12-28P，它是血脑屏障可渗透的无毒，非原纤维合成肽全长Aβ上的apoE结合位点。 Aβ12-28P以高亲和力与apoE结合，阻止其与Aβ结合，但对Aβ聚集没有直接影响。 Aβ12-28P在体内显示出强大的药理作用。它的全身性给药导致两个AD转基因小鼠模型中Aβ斑块和脑淀粉样血管病负担的显着降低以及Aβ的总脑水平的降低。该处理未影响可溶性Aβ馏分或Aβ低聚物的水平，表明体内对apoE /Aβ相互作用的抑制具有增加Aβ清除率高于沉积的净效应，同时不会产生有利于形成毒性低聚物的条件。此外，行为研究表明，用Aβ12-28P治疗可防止转基因动物的记忆力减退。这些发现提供了另一种治疗AD的方法的证据。

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