An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease

Estrogens are neuroprotective, and studies suggest that they may mitigate the pathology and symptoms of Alzheimer's disease (AD) in female models. However, central estrogen effects have not been examined in males in the context of AD. The purpose of this follow-up study was to assess the benefits of a brain-selective 17β-estradiol estrogen prodrug, 10β,17β-hydroxyestra-1,4-dien-3-one (DHED), also in the male APPswe/PS1dE9 double-transgenic mouse model of the disease. After continuously exposing 6-month old animals to DHED for two months, their brains showed decreased amyloid precursor and amyloid-β protein levels. The DHED-treated APPswe/PS1dE9 double transgenic subjects also exhibited enhanced performance in a cognitive task, while 17β-estradiol treatment did not reach statistical significance. Taken together, data presented here suggest that DHED may also have therapeutic benefit in males and warrant further investigations to fully elucidate the potential of targeted estrogen therapy for a gender-independent treatment of early-stage AD. •Treatment of AD-dtg male mice with a brain-selective 17β-estradiol prodrug (DHED) decreased APP.•DHED treatment reduced brain amyloid-β peptide levels.•DHED-treated AD-dtg male mice had improved cognitive performance.•Unlike DHED treatment, 17β-estradiol failed to exert statistically significant effect on learning in AD-dtg male mice.