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Cited by 14Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer’s disease-associated markers in 3xTg-AD mice

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Kapadia, Minesh, Mian, M. Firoz, Ma, Donglai, Hutton, Craig P., Azam, Amber, Narkaj, Klotilda, Cao, Chuanhai, Brown, Breanna +6 more·2021·Alzheimer's Research & Therapy
DOI 10.1186/s13195-020-00745-9PMC PMC7818784

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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.

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Cited by

Sorted by citations

Authors
Kapadia, M., Mian, M. F., Ma, D., Hutton, C. P., Azam, A., Narkaj, K., Cao, C., Brown, B., Michalski, B., Morgan, D., Forsythe, P., Zovkic, I. B., Fahnestock, M., & Sakic, B.
Affiliations
  • McMaster University (CA)
  • University of Toronto (CA)
  • University of South Florida (US)
  • Michigan State University (US)
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-01-20
Volume
13
Issue
1
Pages
30-30
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-020-00745-9
PMC
PMC7818784
OpenAlex
W3118711961
Cited by
14
References
16
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 3 · 2021: 1
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Institute of Neurosciences, Mental Health and Addiction (PJT-149031)
  • Canadian Consortium on Neurodegeneration in Aging
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, 3xTg-AD mice, cyclophosphamide, chronic immunosuppression, systemic autoimmunity, sex differences, macroH2A1, histone variants, soluble amyloid-beta, autoantibodies, regulatory T cells, effector T cells, hepatosplenomegaly, brain-derived neurotrophic factor, tau protein, anxiety, neurodegeneration, epigenetics
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Female, Immunosuppression Therapy, Male, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Epigenesis, Genetic, Mice, Plaque, Amyloid

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