Evidence map›Paper›PMID 41327391›Full record

ArticleBiology of sex differences2025

Gonadal hormones contribute to sex differences in behavior, pathology and epigenetic modifications in the 3×Tg-AD mouse model of Alzheimer's disease.

Wei Song, Samantha D Creighton, Bernadeta Michalski, Juliette Mojgani, Minesh Kapadia, Donglai Ma, Boris Sakic, Iva B Zovkic, Margaret Fahnestock

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Article in Biology of sex differences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

9 authors.

Wei SongDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada.
Samantha D CreightonDepartment of Psychological and Brain Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.
Bernadeta MichalskiDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada.
Juliette MojganiDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada.
Minesh KapadiaToronto Western Hospital, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
Donglai MaDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Boris SakicDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada.
Iva B ZovkicDepartment of Psychological and Brain Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.
Margaret FahnestockDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada. fahnest@mcmaster.ca.

Funding

CIHR CNA-163902CIHR PJT-149031CIHR PJT-156414
6 · The paper itself

Abstract

backgroundSex-dependent differences in prevalence and severity are characteristics of Alzheimer's disease (AD). Using the 3×Tg-AD mouse model, we previously reported that adult males show early behavioral dysfunction, altered epigenetic factors and lack of plaque/tangle pathology. Conversely, adult females retain more severe AD-like pathology and behavior. The present study examines whether gonadal hormones play a role in these differences in current cohorts of 3×Tg-AD mice.

methods3×Tg-AD and wild-type mice were gonadectomized or sham-operated at 3 months of age. After behavioral phenotyping at 6 months of age, the animals were assessed for molecular markers of AD pathology and expression of genes and histone variants associated with neurodegeneration.

resultsIn female transgenic (AD) mice, gonadectomy resulted in poorer spatial learning performance. In contrast, in transgenic male animals, gonadectomy improved spatial learning and memory. Compared to sham-operated AD females, gonadectomized AD females exhibited enhanced expression of mouse (m) Mapt and App genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the mMapt gene, but there was no effect on Aβ

conclusionsIn sum, the results suggest that reduction in serum levels of female gonadal hormones impairs spatial learning capacity, whereas loss of male gonadal hormones enhances spatial learning and memory. In females, gonadectomy reduces binding of the repressive histone variant MacroH2A1 to the mouse Mapt gene and increases expression of the mouse App and Mapt genes without affecting Aβ

Indexed as

Alzheimer DiseaseBehavior, AnimalEpigenesis, GeneticGonadal HormonesSex CharacteristicsAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsDisease Models, AnimalFemaleMaleMiceMice, Inbred C57BLMice, Transgenictau ProteinsAmyloid beta-PeptidesAmyloid beta-Protein PrecursorGonadal Hormonestau Proteins3×Tg-AD miceAlzheimer’s diseaseGonadectomyHistone variantsMacroH2A1Sexual dimorphism

Identifiers

PMID41327391
PMCPMC12797355

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LicenceCC BY
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.