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Background <p>Sex-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.</p> Methods <p>3×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.</p> Results <p>In 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) <i>Mapt</i> and <i>App</i> genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the m<i>Mapt</i> gene, but there was no effect on Aβ<sub>42</sub> or pTau181 levels. In contrast, gonadectomized AD males showed significantly increased macroH2A1 binding at the m<i>Psen1</i> promoter, reduced expression of the <i>App</i> and <i>MacroH2A1</i> genes, and reduced cortical soluble Aβ<sub>42</sub> levels compared to sham-operated AD males.</p> Conclusions <p>In 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 <i>Mapt</i> gene and increases expression of the mouse <i>App</i> and <i>Mapt</i> genes without affecting Aβ<sub>42</sub> or pTau181 levels. Conversely, loss of male gonadal hormones increases binding of MacroH2A1 to the mouse <i>Psen1</i> gene and decreases <i>App</i> expression and Aβ<sub>42</sub> levels but has no effect on tau expression. Our work suggests that adult gonadal hormones contribute to sex differences in AD-like pathology and performance in learning and memory tasks. Moreover, sex-specific differences in AD-like pathology are partially due to the action of histone variants associated with neurodegeneration, such as macroH2A1.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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

摘要

Background

Sex-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.

Methods

3×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.

Results

In 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 Aβ42 or pTau181 levels. In contrast, gonadectomized AD males showed significantly increased macroH2A1 binding at the mPsen1 promoter, reduced expression of the App and MacroH2A1 genes, and reduced cortical soluble Aβ42 levels compared to sham-operated AD males.

Conclusions

In 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 Aβ42 or pTau181 levels. Conversely, loss of male gonadal hormones increases binding of MacroH2A1 to the mouse Psen1 gene and decreases App expression and Aβ42 levels but has no effect on tau expression. Our work suggests that adult gonadal hormones contribute to sex differences in AD-like pathology and performance in learning and memory tasks. Moreover, sex-specific differences in AD-like pathology are partially due to the action of histone variants associated with neurodegeneration, such as macroH2A1.