Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.
Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.
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DOI：
10.7150/thno.79898
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发表时间：
2023
期刊：
影响因子：
12.4
通讯作者：
Konofagou EE
中科院分区：
文献类型：
--
作者：
Karakatsani ME;Ji R;Murillo MF;Kugelman T;Kwon N;Lao YH;Liu K;Pouliopoulos AN;Honig LS;Duff KE;Konofagou EE
理论基础：在没有任何治疗药物的情况下，聚焦超声(FUS)结合微泡的双侧超声治疗已被证明可以分别减少不同阿尔茨海默病(AD)模型小鼠的海马结构和内嗅皮层中的淀粉样斑块和过度磷酸化的tau蛋白。然而，这两种病理在人类疾病中同时表达。因此，这项研究的目的是调查在两种病理情况下重复双侧超声的效果。方法：在此，我们研究其在同时具有这两种病理的脑中的功能和形态结果。11只表达人淀粉样β蛋白和人tau蛋白的3xTg-AD系转基因小鼠(14个月大)和11只年龄匹配的野生型小鼠接受了每周四次覆盖海马区的双侧声波检查，然后进行工作记忆测试。然后，采用免疫组织化学和免疫分析(Western印迹和ELISA法)评估淀粉样β蛋白和人tau蛋白的变化。此外，我们提供了使用神经导航引导的FUS系统对AD患者进行超声检查的临床试验的初步数据(NCT04118764)。结果：有趣的是，接受FUS的野生型和转基因动物都改善了工作记忆，并在逃生平台象限花费了显著更多的时间，其中野生型动物花费了43.2%(假：37.7%)，转基因动物花了35.3%(假：31.0%)在目标象限。此外，转基因动物的这种行为改善与tau影响的神经元长度减少58.3%和总tau水平减少27.2%相关。淀粉样斑块的数量、体积和总负荷也总体上减少了。始终如一的是，一项涉及AD患者的临床试验的初步数据显示，治疗3周后，治疗侧大脑半球的淀粉样PET信号与基线相比下降了1.8%。结论：首次显示双侧FUS诱导的血脑屏障开放显著且同时改善了两种共存的病理改变，这转化为复杂AD转基因动物空间记忆的改善。认知改善程度与血脑屏障开放程度显著相关。非转基因动物也首次表现出类似的记忆改善，表明无论是否存在AD病理，BBB开放都会对神经元功能产生好处。被研究的降低这两种病理的潜在作用机制是胆固醇代谢，特别是LRP1B受体，在FUS诱导的BBB开放后，转基因小鼠的LRP1B受体的表达水平增加。初步的临床证据支持，啮齿类动物的β淀粉样蛋白减少可以移植到人类身上，治疗后的大脑半球显示出显著的淀粉样蛋白减少。
Rationale: Bilateral sonication with focused ultrasound (FUS) in conjunction with microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein in the hippocampal formation and the entorhinal cortex in different mouse models of Alzheimer's disease (AD) without any therapeutic agents. However, the two pathologies are expressed concurrently in human disease. Therefore, the objective of this study is to investigate the effects of repeated bilateral sonications in the presence of both pathologies. Methods: Herein, we investigate its functional and morphological outcomes on brains bearing both pathologies simultaneously. Eleven transgenic mice of the 3xTg-AD line (14 months old) expressing human amyloid beta and human tau and eleven age-matched wild-type littermates received four weekly bilateral sonications covering the hippocampus followed by working memory testing. Afterwards, immunohistochemistry and immunoassays (western blot and ELISA) were employed to assess any changes in amyloid beta and human tau. Furthermore, we present preliminary data from our clinical trial using a neuronavigation-guided FUS system for sonications in AD patients (NCT04118764). Results: Interestingly, both wild-type and transgenic animals that received FUS experienced improved working memory and spent significantly more time in the escape platform-quadrant, with wild-type animals spending 43.2% (sham: 37.7%) and transgenic animals spending 35.3% (sham: 31.0%) of the trial in the target quadrant. Furthermore, this behavioral amelioration in the transgenic animals correlated with a 58.3% decrease in the neuronal length affected by tau and a 27.2% reduction in total tau levels. Amyloid plaque population, volume and overall load were also reduced overall. Consistently, preliminary data from a clinical trial involving AD patients showed a 1.8% decrease of amyloid PET signal 3-weeks after treatment in the treated hemisphere compared to baseline. Conclusion: For the first time, it is shown that bilateral FUS-induced BBB opening significantly and simultaneously ameliorates both coexistent pathologies, which translated to improvements in spatial memory of transgenic animals with complex AD, the human mimicking phenotype. The level of cognitive improvement was significantly correlated with the volume of BBB opening. Non-transgenic animals were also shown to exhibit similar memory amelioration for the first time, indicating that BBB opening results into benefits in the neuronal function regardless of the existence of AD pathology. A potential mechanism of action for the reduction of the both pathologies investigated was the cholesterol metabolism, specifically the LRP1b receptor, which exhibited increased expression levels in transgenic mice following FUS-induced BBB opening. Initial clinical evidence supported that the beta amyloid reduction shown in rodents could be translatable to humans with significant amyloid reduction shown in the treated hemisphere.
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影响因子：
10.6
作者：
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通讯作者：
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影响因子：
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DOI：
10.1016/j.trci.2019.05.008
发表时间：
2019-01-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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