Transcranial scanning ultrasound combined with intravenously injected microbubbles (SUS^+MB) has been shown to transiently open the blood–brain barrier and reduce the amyloid-β (Aβ) pathology in the APP23 mouse model of Alzheimer's disease (AD). This has been accomplished through the activation of microglial cells; however, their response to the SUS treatment is incompletely understood. Here, wild-type (WT) and APP23 mice were subjected to SUS^+MB, using nonsonicated mice as sham controls. After 48 h, the APP23 mice were injected with methoxy-XO4 to label Aβ aggregates, followed by microglial isolation into XO4⁺ and XO4⁻ populations using flow cytometry. Both XO4⁺ and XO4⁻ cells were subjected to RNA sequencing and transcriptome profiling. The analysis of the microglial cells revealed a clear segregation depending on genotype (AD model vs. WT mice) and Aβ internalization (XO4⁺ vs. XO4⁻ microglia), but interestingly, no differences were found between SUS^+MB and sham in WT mice. Differential gene expression analysis in APP23 mice detected 278 genes that were significantly changed by SUS^+MB in the XO4⁺ cells (248 up/30 down) and 242 in XO⁻ cells (225 up/17 down). Pathway analysis highlighted differential expression of genes related to the phagosome pathway and marked upregulation of cell cycle-related transcripts in XO4⁺ and XO4- microglia isolated from SUS^+MB-treated APP23 mice. Together, this highlights the complexity of the microglial response to transcranial ultrasound, with potential applications for the treatment of AD.

中文翻译：

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从用扫描超声治疗的阿尔茨海默病小鼠模型中分离出的小胶质细胞的转录特征

在阿尔茨海默病 (AD) 的 APP23 小鼠模型中，经颅扫描超声结合静脉注射微泡 (SUS ^+MB ) 已被证明可以暂时打开血脑屏障并减少淀粉样蛋白-β (Aβ) 病理学。这是通过激活小神经胶质细胞实现的；然而，他们对 SUS 治疗的反应尚不完全清楚。在这里，野生型 (WT) 和 APP23 小鼠接受 SUS ^+MB，使用非超声处理小鼠作为假对照。48 小时后，APP23 小鼠注射甲氧基-XO4 以标记 Aβ 聚集体，然后使用流式细胞术将小胶质细胞分离成 XO4 ⁺和 XO4 ^-群体。XO4 ⁺和 XO4 ^-对细胞进行 RNA 测序和转录组分析。对小胶质细胞的分析揭示了明显的分离，这取决于基因型（AD 模型与 WT 小鼠）和 Aβ 内化（XO4 ⁺与 XO4 ^{−小胶质细胞），但有趣的是，在 WT 小鼠中，SUS +MB}和假小鼠之间没有发现差异. APP23 小鼠的差异基因表达分析检测到XO4 ⁺细胞中的278 个基因被 SUS ^+MB显着改变（248 个向上/30 个向下）和 XO ^-细胞中的 242 个（225 个向上/17 个向下）。通路分析突出了与吞噬体通路相关的基因的差异表达和 XO4 ^{+中细胞周期相关转录物的显着上调和从 SUS +MB}处理的APP23 小鼠中分离的 XO4- 小胶质细胞。总之，这突出了小胶质细胞对经颅超声反应的复杂性，以及治疗 AD 的潜在应用。