Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
3xTg-AD mice display manifestations of systemic autoimmunity, including splenomegaly, hepatomegaly, elevated serum autoantibodies, reduced hematocrit, and elevated double-negative T splenocytes, which are all exacerbated in 3xTg-AD males.
“Marchese et al. and Kapadia et al. have provided strong evidence that 3xTg-AD mice display manifestations of systemic autoimmunity, including splenomegaly, hepatomegaly, elevated serum autoantibodies, reduced hematocrit, and elevated double-negative (CD4-/CD8-) T splenocytes, which are all exacerbated in 3xTg-AD males [26, 27].”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [27]
Sections 3.1 and 3.3 report more severe splenomegaly, higher serum autoantibodies, and lower hematocrit in six-month-old 3xTg-AD males than females. Section 3.2 reports reduced CD3+, CD8+, and CD4+ splenic T-cell populations, but does not report elevated double-negative T splenocytes; the retrieved organ-weight results do not report hepatomegaly. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThese results align with published literature and reinforce the translatability of the 3xTg-AD model.
“Together, these results align with published literature [20, 21, 23, 24, 26, 27] and reinforce the translatability of the 3xTg-AD model.”
3xTg-AD males exhibit a sex-dependent spontaneous autoimmune response.
“This finding complements the strong body of evidence that 3xTg-AD males exhibit a sex-dependent spontaneous autoimmune response.”
Kapadia et al. further revealed that these manifestations of autoimmunity are exacerbated in 3xTg-AD males relative to females at 6 months of age.
“Kapadia et al. further revealed that these manifestations of autoimmunity are exacerbated in 3xTg-AD males relative to females at 6 months of age [27].”
Hepatomegaly has been previously reported in the 3xTg-AD model.
“Hepatomegaly has been previously reported in the 3xTg-AD model [26, 27, 52]”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [27]
Section 3.1 (Body and organ weights; page unavailable) reports splenomegaly in 3xTg-AD mice, not hepatomegaly. Searches for hepatomegaly, liver enlargement, and liver weight found no passage in our copy addressing liver enlargement. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.040 · Cited by 1,294 · see citing works
Ferreira, S. T., Lourenco, M. V., Oliveira, M. M., & De Felice, F. G. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00191 · Cited by 373 · see citing works
Critical Role of Histone Turnover in Neuronal Transcription and Plasticity
Maze, I., Wenderski, W., Noh, K.-M., Bagot, R. C., Tzavaras, N., Purushothaman, I., Elsässer, S. J., Guo, Y., Ionete, C., Hurd, Y. L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.014 · Cited by 306 · see citing works
Janelsins, M. C., Mastrangelo, M. A., Oddo, S., LaFerla, F. M., Federoff, H. J., & Bowers, W. J. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-23 · Cited by 260 · see citing works
Ungar, L., Altmann, A., & Greicius, M. D. (2014) · Brain Imaging and Behavior · doi:10.1007/s11682-013-9272-x · Cited by 246 · see citing works
Sex and Gender Differences in Alzheimer's Disease: Recommendations for Future Research
Carter, C. L., Resnick, E. M., Mallampalli, M., & Kalbarczyk, A. (2012) · Journal of Women's Health · doi:10.1089/jwh.2012.3789 · Cited by 231 · see citing works
Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice
Sy, M., Kitazawa, M., Medeiros, R., Whitman, L., Cheng, D., Lane, T. E., & LaFerla, F. M. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.02.012 · Cited by 210 · see citing works
Stevens, L. M., & Brown, R. E. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.10.033 · Cited by 92 · see citing works
Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice
Perez, S. E., He, B., Muhammad, N., Oh, K.-J., Fahnestock, M., Ikonomovic, M. D., & Mufson, E. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.002 · Cited by 80 · see citing works
Self-citationAberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior
Lepack, A. E., Bagot, R. C., Peña, C. J., Loh, Y.-H. E., Farrelly, L. A., Lu, Y., Powell, S. K., Lorsch, Z. S., Issler, O., Cates, H. M., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608270113 · Cited by 63 · see citing works
The Role of Microglia in Antibody-Mediated Clearance of Amyloid-Beta from the Brain
Morgan, D. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787601821 · Cited by 58 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [22][22] Theofilopoulos AN (1992) Murine models of lupus In Systemic lupus erythematosus , Lahita RG, ed. Churchill Livingstone, New York, pp. 121-194. -
Cited by
Sorted by citations
Barber, A. J., del Genio, C. L., Swain, A. B., Pizzi, E. M., Watson, S. C., Tapiavala, V. N., Zanazzi, G. J., & Gaur, A. B. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01492-x · Cited by 41 · see citing works
- Authors
- Kapadia, M., Mian, M. F., Michalski, B., Azam, A. B., Ma, D., Salwierz, P., Christopher, A., Rosa, E., Zovkic, I. B., Forsythe, P., Fahnestock, M., & Sakic, B.
- Affiliations
- McMaster University (CA)
- University of Toronto (CA)
- Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2018-05-08
- Volume
- 63
- Issue
- 3
- Pages
- 1191-1205
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2800555908
- Cited by
- 29
- References
- 11
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 8 · 2018: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- MacSphere (McMaster University) (submittedVersion)
- MacSphere (McMaster University)
- Funders
- Canadian Institutes of Health Research (149031_1)
- 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
- 3xTg-AD mice, Alzheimer's disease model
- MeSH terms
- Alzheimer Disease, Animals, Autoantibodies, Disease Models, Animal, DNA, Female, Gene Expression Regulation, Hematocrit, Histones, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nuclear Proteins, Organ Size, Sex Characteristics, Spleen, T-Lymphocytes, Autoimmunity, Antigens, CD, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Mice, Presenilin-1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
