Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice

Article type: Research Article

Authors: Kapadia, Minesh^a | Mian, M. Firoz^b | Michalski, Bernadeta^a | Azam, Amber B.^e | Ma, Donglai^c | Salwierz, Patrick^d | Christopher, Adam^d | Rosa, Elyse^a | Zovkic, Iva B.^e | Forsythe, Paul^b | Fahnestock, Margaret^a | Sakic, Boris^{a; *}

Affiliations: [a] Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada | [b] Department of Medicine, McMaster University, Hamilton, ON, Canada | [c] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada | [d] Biochemistry and Bachelor of Health Sciences Undergraduate programs, McMaster University, Hamilton, ON, Canada | [e] Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada

Correspondence: [*] Correspondence to: Boris Sakic, PhD, Department of Psychiatry and Behavioral Neurosciences, McMaster University, Psychology Building Rm. 303, 1280 Main St. West, Hamilton, ON L8S 4K1, Canada. Tel.: +1 905 518 7833; E-mail: sakic@mcmaster.ca.

Abstract: The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer’s disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.

Keywords: 3xTg-AD mice, Alzheimer’s disease, autoantibodies, BDNF, histone variants, protective autoimmunity, soluble amyloid-beta, tau protein, T-lymphocytes

DOI: 10.3233/JAD-170779

Journal: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1191-1205, 2018