Work

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

Year: 2022

Type: article

Abstract: Rationale Intracranial scanning ultrasound combined with intravenously injected microbubbles (SUS +MB ) has been shown to transiently open the blood-brain barrier and reduce amyloid-β (Aβ) pathology in the APP23 mouse model of Alzheimer’s disease (AD). This has been accomplished, at least in part, through the activation of microglial cells; however, their response to the SUS treatment is only incompletely understood. Methods Wild-type (WT) and APP23 mice were subjected to SUS +MB , using non-SUS +MB -treated mice as sham controls. After 48 hours, 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 their transcriptome was analyzed through a bioinformatics pipeline. Results The transcriptomic analysis of the microglial cells revealed a clear segregation depending on genotype (AD model versus WT mice), as well as treatment (SUS +MB versus sham) and Aβ internalization (XO4 + versus XO4 - microglia). Differential gene expression analysis 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). Not surprisingly given previous findings of increased phagocytosis of plaques following SUS +MB , the pathway analysis highlighted that the treatment induced an enrichment in genes related to the phagosome pathway in XO4 + microglia; however, when comparing SUS +MB to sham, the analysis revealed an enrichment in genes involved in the cell cycle in both the XO4 + and XO4 - microglial population. Conclusion Our data provide a comprehensive analysis of microglia in an AD mouse model subjected to ultrasound treatment as a function of Aβ internalization, one of the defining hallmarks of AD. Several differentially expressed genes are highlighted, pointing to an ultrasound-induced activation of cell cycle mechanisms in microglial cells isolated from APP23 mice treated with SUS +MB . Graphical abstract

Source: Bioengineering & Translational Medicine

DOI: 10.1002/btm2.10329