Sex-Dependent Differences in Serum Autoantibody Levels in the 3×Tg-AD Model of Alzheimer’s Disease

Abstract Sex-dependent discrepancies in disease prevalence and serum autoantibody levels are observed in patients and animal models of Alzheimer’s disease (AD). The present study examines whether gonadal hormones play a role in sex differences in serum autoantibody levels in the 3×Tg-AD mouse model of AD. 3×Tg-AD and wild-type (WT) mice were gonadectomised or sham-operated at 3 months of age. After behavioural phenotyping at 6 months of age, the animals were assessed for serum autoantibodies by indirect immunofluorescence for antinuclear antibodies (ANA) and by line-immunoblot assay for an additional 16 monospecific autoantibodies including anti-nucleosome antibodies. There were significant differences between the strains in ANA levels, with the major target antigens confirmed as nucleosomes. The results of ANA and anti-nucleosome assays were combined for further analysis. Further analysis revealed: 1) the level of serum autoantibodies in male 3×Tg-AD mice was higher than in female 3×Tg-AD animals, and this was not altered by orchiectomy. 2) sham-operated 3×Tg-AD female mice displayed a significantly lower level of serum autoantibodies than sham-operated WT females. 3) ovariectomy further reduced the level of serum autoantibodies in female 3×Tg-AD mice. The results suggest that dissimilar levels of serum autoantibodies in 3xTg-AD mice are a sex-dependent phenomenon and that female hormones play a role in regulation of their synthesis. Funded by grant #SVB-158618 from the Canadian Institutes of Health Research to MF.