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首页> 外文期刊>Neuron >Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies
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Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies

机译：阿尔茨海默氏病模型缺乏广泛的血脑屏障破坏：专注于治疗性抗体

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摘要

The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer's disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease.
机译：血脑屏障（BBB）限制了大脑对治疗性抗体的摄取。据信，BBB在阿尔茨海默氏病（AD）中被破坏，事实上可能增加药物的渗透性。在这里，我们比较了AD小鼠模型中全身剂量抗体（抗转铁蛋白受体[TfR]双特异性相对于对照抗体）的主动摄取与被动摄取。我们首先在多发性硬化的小鼠模型中确认了BBB破坏作为阳性对照。重要的是，我们发现在AD的小鼠模型（包括PS2-APP，Tau转基因和APOE4敲入小鼠）中，BBB的通透性得到了极大的保留。在小鼠模型或AD的人类病例中，TfR的脑水平类似于对照，表明TfR双特异性靶标的参与不受限制。此外，与年龄匹配的对照组相比，来自人AD脑的梗塞也有相似的发生。这些结果质疑了普遍持有的观点，即BBB在AD中受到很大破坏，引起了人们对疾病中药物渗透性假设的担忧。

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