Aducanumab 与超声扫描对 APP23 阿尔茨海默病模型淀粉样斑块和行为影响的比较研究。
A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease.
机构信息
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
出版信息
Alzheimers Res Ther. 2021 Apr 9;13(1):76. doi: 10.1186/s13195-021-00809-4.
BACKGROUND
Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.
METHODS
In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13-22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.
RESULTS
We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.
背景
Aducanumab 是一种抗淀粉样蛋白-β（Aβ）抗体，在阿尔茨海默病（AD）试验中已证实可减少淀粉样蛋白病理学；然而，它是否也能改善认知存在争议，有人认为这需要在大脑中累积足够高剂量的抗体。相比之下，治疗性超声仅在 AD 临床试验中开始进行研究。我们之前已经表明，结合静脉内注射微泡的超声扫描（SUS），可以暂时且安全地打开血脑屏障（BBB），去除淀粉样蛋白并恢复 APP23 小鼠的认知功能。然而，尚未直接测试 SUS 的效果与免疫疗法相比如何，或者联合治疗是否更有效。
方法
在包含四个治疗组的一项研究中，我们测试了 Aducanumab 类似物 Adu 的疗效，与 SUS 进行了比较，并作为联合疗法，在 APP23 小鼠（13-22 个月大）中进行了测试，使用假手术作为对照。主动回避测试（APA）用于测试空间记忆，组织学和 ELISA 用于测量淀粉样蛋白。还测定了大脑中的抗体水平。
结果
我们发现 Adu 和 SUS 均可减少海马体中的总斑块面积，而联合治疗则没有观察到累加效应（SUS+Adu）。在皮质中，尽管 Adu 或 SUS 均有降低总斑块面积的趋势，但仅联合治疗与假手术相比，总斑块面积有统计学意义的降低。只有 SUS 和 SUS+Adu 组中的动物将斑块负荷从高于 10%降低到低于 1%。仅 SUS+Adu 组的空间记忆有明显改善，并且在该组中，在治疗后 3 天测量时，Adu 的水平比单独接受 Adu 的那些小鼠高 5 倍。这些发现表明，SUS 应被视为 AD 的治疗选择。或者，使用 Aducanumab 联合超声增加大脑中抗体水平的联合试验可能是必要的。
Zotero 插件