Deficiency of Complement Component C1Q Prevents Cerebrovascular Damage and White Matter Loss in a Mouse Model of Chronic Obesity

C1QA and C3 deposits increase in white matter tracts of WD-fed mice. A, Increased C1QA immunoreactivity in the corpus callosum of WD-fed compared with CD-fed mice colocalized with IBA1⁺ cells and MBP⁺ myelin. B, Increased C3 immunoreactivity in the corpus callosum of WD-fed compared with CD-fed mice colocalized with MBP⁺ myelin. White dotted lines indicate the boundary between the CA1 region of the hippocampus and the corpus callosum. Scale bars: 40 μm.

WD-induced obesity and metabolic profiles were not altered by C1QA deficiency. A–D, Weight and adiposity increased in WD-fed mice independent of genotype and sex. E–H, No differences were detected in total cholesterol (E, G) and triglycerides (F, H) between WD-fed WT and C1qa KO mice. I–L, LDL and HDL plasma levels in male and female WD-fed mice were not changed by C1QA deficiency. M, N, Fatty acids plasma levels were not altered by C1QA deficiency. Data are presented as mean ± SEM, n ≥ 5, *p < 0.05, **p< 0.01, ***p< 0.001, ****p < 0.0001 by one-way ANOVA with Tukey’s post hoc test. n.s., not significant.

C1QA deficiency did not alter glucose or insulin tolerance in obese mice. A–D, No significant changes were detected in glucose tolerance between genotypes and sex. Only WD-fed male mice showed a moderate impaired glucose tolerance that was prevented by C1QA deficiency (B). E–H, No changes were observed in the ITT between groups. Data are presented as mean ± SEM, n ≥ 5, *p < 0.05 by one-way ANOVA with Tukey’s post hoc test.

C1QA deficiency prevented WD-induced cognitive deficits in male mice. A, B, WD-fed male mice showed a significant impairment in % correct alternation (A), which was not due to reductions in total activity as measured by total arm entries (B). However, C1qa KO WD-fed male mice showed no significant impairment in % correct alternations when compared with CD-fed male mice. C, D, No differences were observed in % correct alternations between CD-fed and WD-fed female mice. E, G, Activity levels in the open field as measured by cumulative distance traveled revealed no differences between groups in both male and female mice. F, H, Grip strength measurements were not different between groups in both male and female mice. Data are presented as mean ± SEM, n ≥ 8, *p < 0.05 by one-way ANOVA with Tukey’s post hoc test.

C1QA deficiency prevented WD-diet induced cerebrovascular damage. A–C, WD-induced decrease in PDGFRβ⁺ pericytes in WT mice was prevented by C1QA deficiency (A, B). The decrease of laminin⁺ capillary density caused by WD was prevented by C1QA deficiency (A, C). Representative images are from a region of the parietal cortex (above the CA1 region of the hippocampus; see Materials and Methods). Data are presented as mean ± SEM, n ≥ 5, *p < 0.05 by one-way ANOVA with Tukey’s post hoc test. Scale bars: 30 μm. n.s., not significant.

WD-induced myeloid cell activation was prevented by C1QA deficiency. A, B, The increase in the number of IBA1⁺ (A, B, E) and CD68⁺ (A, B, F) surfaces in WD-fed WT was prevented by C1QA deficiency. C–D, Representative examples of IBA1⁺CD68⁺ microglia. Microglia from WD-fed WT mice showed the greatest levels of CD68. Representative images for quantification are shown that contain a portion of the CA1 of the hippocampus, the corpus callosum and the parietal cortex. Data are presented as mean ± SEM, n ≥ 4, **p < 0.01 by one-way ANOVA with Tukey’s post hoc test. Scale bars: 30 μm (A, B) and 10 μm (C, D).