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Background <p>Alzheimer’s disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain’s resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression.</p> Methods <p>We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting.</p> Results <p>We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females.</p> Conclusions <p>Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.</p>

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Neonatal estradiol influences regional gene expression for early sex-specific inflammatory responses in the 5xFAD mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Phaedra R. Keller-Norrell,
  • Brad T. Casali,
  • Logan N. Yost,
  • Erin G. Reed

摘要

Background

Alzheimer’s disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain’s resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression.

Methods

We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting.

Results

We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females.

Conclusions

Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.