Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice

Yaoyao Qin,Weixing Xu,Dong An,Xiaoli Wang,Ling Chen,Xiuting Qi,Lei Chen,Sha Sha

doi:10.3389/fnagi.2020.00240

Abstract

It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer’s disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, β-amyloid (Aβ) accumulation, telomerase activity, and hippocampal-dependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aβ accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aβ levels accompanied by elevated p75 neurotrophin receptor (p75NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aβ/p75NTR-induced NSC overproliferation and preserves telomerase activity.

Highlights

The risk for Alzheimer’s disease (AD) is associated with age-related loss of ovarian hormones in women (Marongiu, 2019)
The administration of M-E2 or L-E2 had no effect on TERT expression or telomerase activity in OVX-10m-APP/PS1 mice. These results indicate that telomerase activity declines in the Aβimpaired hippocampus, which is exacerbated by E2 deficiency; this is reversed by early period E2 treatment
Consistent with the evidence supporting the existence of a critical period for the benefit of estrogen replacement therapy (ERT) on cognitive function in postmenopausal women with AD (Vedder et al, 2014), here, we showed in AD model mice that E2 treatment in the early, but not in the late period post-OVX, prevented cognitive decline

Summary

Introduction

The risk for Alzheimer’s disease (AD) is associated with age-related loss of ovarian hormones in women (Marongiu, 2019). Experiments in aged nonhuman primates and rodents have revealed that 17β-estradiol (E2) treatment following ovariectomy can improve cognitive function (Baxter et al, 2018; Pollard et al, 2018) and alleviate cognitive decline in aged animals with long-term E2 deficiency (Luine, 2014). This critical treatment window may be related to changes in brain responsiveness to E2. There is increasing evidence that E2 can alter hippocampal structure and function (Frick et al, 2015), with long-term administration of E2 at physiologic doses reducing Aβ accumulation in 3xTg-AD mice (Carroll et al, 2007)

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