Minesh Kapadia1, M Firoz Mian2, Donglai Ma3, Craig P Hutton4, Amber Azam5, Klotilda Narkaj5, Chuanhai Cao6, Breanna Brown6, Bernadeta Michalski1, David Morgan7, Paul Forsythe2, Iva B Zovkic5, Margaret Fahnestock1, Boris Sakic8. 1. Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada. 2. Department of Medicine, McMaster University, Hamilton, ON, Canada. 3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. 4. Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, ON, Canada. 5. Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada. 6. Department of Pharmaceutical Science, University of South Florida, Tampa, FL, USA. 7. Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. 8. Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada. sakic@mcmaster.ca.
Abstract
BACKGROUND: Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. METHODS: Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. RESULTS: Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. CONCLUSION: The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.
BACKGROUND: Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-ADmouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. METHODS: Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. RESULTS: Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. CONCLUSION: The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-ADmice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.
Entities:
Keywords:
3xTg-AD mice; Alzheimer’s disease; Amyloid-beta; Autoantibodies; Autoimmunity; BDNF; Cyclophosphamide; Histone variants; Sex; T lymphocytes; Tau
Authors: Minesh Kapadia; M Firoz Mian; Bernadeta Michalski; Amber B Azam; Donglai Ma; Patrick Salwierz; Adam Christopher; Elyse Rosa; Iva B Zovkic; Paul Forsythe; Margaret Fahnestock; Boris Sakic Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472
Authors: Edward K L Chan; Jan Damoiseaux; Orlando Gabriel Carballo; Karsten Conrad; Wilson de Melo Cruvinel; Paulo Luiz Carvalho Francescantonio; Marvin J Fritzler; Ignacio Garcia-De La Torre; Manfred Herold; Tsuneyo Mimori; Minoru Satoh; Carlos A von Mühlen; Luis E C Andrade Journal: Front Immunol Date: 2015-08-20 Impact factor: 7.561