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Fig. 4 | Acta Neuropathologica Communications

Fig. 4

From: Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease

Fig. 4

Inhibition of JAK2-STAT3-mediated astrocyte reactivity reduces amyloid load in APP mice without impacting microglial cells a, Representative images of BAM10+ amyloid plaques (white) automatically delineated in yellow in APP-GFP, APP-SOCS3 and APP-JAK2ca mice. b, The number of hippocampal BAM10+ plaques is significantly decreased by SOCS3 (N = 9–8) and increased by JAK2ca in APP mice (N = 6–6). SOCS3 and JAK2ca effects were measured in two independent cohorts. c, The average size of individual BAM10+ amyloid plaque is similar between groups. d, Dosage of Aβ40 and Aβ42 peptide concentrations in Triton-X100-soluble protein homogenates from the hippocampus of APP-GFP (N = 10 or 6), APP-SOCS3 (N = 8) and APP-JAK2ca mice (N = 6). Aβ40 and 42 levels are not significantly different between groups. e, IBA1+ microglial cells (red, arrowheads) in contact with a MXO4+ amyloid plaque (blue). f, The number of microglia per plaque is similar between APP-GFP and APP-SOCS3 mice. N = 10–8. g, Confocal images of MXO4+ material (blue) in IBA1+ microglial cells (red). Microglial cells in contact with plaques either display MXO4 staining (white arrowhead) at the membrane, in the cytosol or are MXO4. h, The proportion of these three classes of microglial cells is not different between groups. N = 10–8. i, Experimental design to monitor Aβ phagocytosis. WT-GFP (N = 10), APP-GFP (N = 6) and APP-SOCS3 (N = 8) mice were injected with MXO4, 3 h before sacrifice. After staining, hippocampal CD11b+/CD45+ microglia and GFP+ astrocytes were analyzed by FACS. j, Representative gates to analyze MXO4+ amyloid uptake in astrocytes and microglia. There are 20% MXO4+ microglial cells in both APP-GFP and APP-SOCS3 groups and no MXO4+ astrocytes. k, No difference in the MXO4 median fluorescent intensity (MFI) is observed between APP-GFP and APP-SOCS3 microglial cells. l-m, RT-qPCR analysis on microglial cells acutely isolated from the hippocampus of 12 month-old WT-GFP, APP-GFP and APP-SOCS3 mice. l mRNA levels of Ctss and C1qb, two microglial homeostatic genes, is similar in all groups. m, Apoe and Trem2 mRNA levels are higher in phagocytic MXO4+ microglia than non-phagocytic MXO4 microglia, while Tmem119 levels are lower in MXO4+ microglia. This transcriptional profile is reminiscent of DAM microglia [34]. Astrocyte de-activation by SOCS3 does not impact the transcriptional profile of either type of microglia. N = 3–8/group. b, d, h, Student t test. c, f, k, Kruskall-Wallis test. l, m, One way ANOVA to compare the 3 groups within MXO4 cells and Student t test to compare two groups within MXO4+ cells. Mann-Whitney test to compare MXO4+ and MXO4 microglial cells within APP-GFP or APP-SOCS3 groups. * p < 0.05, ** p < 0.01

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