Fig. 5: Sex-dependent effects of CSF1R are not caused by peripheral toxicity.

a Schematic of chronic treatment of Tg2541 mice from 2–7 mo of age with PLX73086 (200 mg/kg oral), a non-brain penetrant analog of PLX3397 and PLX5622. b Body weights of female or male T2541 mice treated with PLX73086. c, d Plasma concentration of NfL in female (c) or male (d) Tg2541 mice treated with vehicle or PLX73086. e Schematic of chronic treatment of wild type (Wt) mice from 2–7 mo of age with PLX73086 (200 mg/kg oral). f Body weights of female or male Wt mice treated with PLX73086. In (b and f), differences in weight between vehicle and PLX73086 treatment in male or female mice were evaluated by two-way repeated measures ANOVA and P values are shown. Each symbol represents an individual mouse and lines indicate group means. g, h Plasma concentration of NfL in female (g) or male (h) Wt mice treated with vehicle or PLX73086. In (c, d, g, and h), the differences between vehicle or PLX3397 treatment were evaluated by non-linear regression using quadratic models. Each symbol represents an individual mouse and the best-fit lines and statistical results are shown. i Schematic of terminal treatment of Tg2541 mice from 2 mo of age until death with PLX3397. j Representative histopathology images of liver sections of Tg2541 mice receiving terminal treatment with vehicle or PLX3397, stained with hematoxylin and eosin (H&E), Masson’s trichrome, or Picosirius red. High magnification insets are shown of the regions outlined with a white box. Scale bars, 200 µm. H&E and Masson’s trichrome images are representative of eight vehicle-treated mice (two females and six males) and 12 PLX3397-treated mice (four females and eight males) analyzed. Sirius red images shown are representative of images collected and analyzed for all mice shown in panel (k). k Sirius red-stained liver sections of Tg2541 mice that received acute or terminal treatment with vehicle or PLX3397 were quantified for percent positive area. The acute and terminal treatment groups were combined for the analysis due to a limited sample size of terminal treatment groups and because the group means were similar for the two treatment paradigms. Mice receiving terminal treatment are shown as black symbols and mice receiving acute treatment are shown as purple or green symbols. n = 10 female vehicle, 14 female PLX3397, 17 male vehicle, and 16 male PLX3397-treated mice. l Alkaline phosphatase (ALP) levels were measured at eight months of age in the plasma of Tg2541 mice receiving midbrain inoculation of diluent at 2.5 mo of age and then treated with vehicle or PLX3397 until death. The data are presented as a percent change from ALP levels at two months of age (prior to treatment) in the same mice. n = 8 female vehicle, 7 female PLX3397, 8 male vehicle, and 8 male PLX3397-treated mice. In (k and l), the differences between vehicle and PLX3397 treatment were evaluated by ANOVA with Holm-Šidák post hoc analysis and P values are shown. Each symbol represents an individual mouse and error bars indicate the s.d. of the mean. Source data are provided as a Source Data file.