Transcriptional signature in microglia isolated from an Alzheimers disease mouse model treated with scanning ultrasound

RationaleIntracranial scanning ultrasound combined with intravenously injected microbubbles (SUS+MB) has been shown to transiently open the blood-brain barrier and reduce amyloid-{beta} (A{beta}) pathology in the APP23 mouse model of Alzheimers 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. MethodsWild-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 A{beta} 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. ResultsThe 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 A{beta} 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. ConclusionOur data provide a comprehensive analysis of microglia in an AD mouse model subjected to ultrasound treatment as a function of A{beta} 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/473590v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@9ae94org.highwire.dtl.DTLVardef@1a48d22org.highwire.dtl.DTLVardef@2dcb9dorg.highwire.dtl.DTLVardef@92dfb2_HPS_FORMAT_FIGEXP M_FIG C_FIG