Transcriptional signature in microglia isolated from an Alzheimer's disease mouse model treated with scanning ultrasound

Abstract

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 Aβaggregates, followed by microglial isolation into XO4⁺ and XO4‾ populations using flow cytometry. Both XO4⁺ and XO4‾ cells were subjected to RNA sequencing and transcriptome pro-filing. The analysis of the microglial cells revealed a clear segregation depending on genotype (AD model vs. WT mice) and Aβinternalization (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.