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

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-monthold 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 hippocampaldependent 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 (p75 NTR) 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 p75 NTR 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/p75 NTR-induced NSC overproliferation and preserves telomerase activity.

The Potential Roles of Redox Enzymes in Alzheimer’s Disease: Focus on Thioredoxin

“…Wang, Wang, et al., 2019), the upregulation of Trx-1 by estrogen can further inhibit TXNIP-induced oxidative stress by Aβ and activate AMPK signaling(Table 2) (Pan et al., 2020). Prospective and case-control studies have demonstrated that estrogen replacement therapy can effectively reduce cognitive deficits in some but not all postmenopausal women(Qin et al., 2020).…”

Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

“…Estrogen replacement therapy (ERT) can effectively reduce the cognitive impairment of some but not all postmenopausal women (Espeland et al, 2004;Vedder et al, 2014). Many evidence show that the effectiveness of ERT depends on its application in a critical period (Zandi et al, 2002;Qin et al, 2020). However, large clinical trials have indicated that HRT increases the risk of breast cancer and stroke (Beral, 2003;Stahlberg et al, 2004;Henderson and Lobo, 2012).…”

Impact of Testosterone on Alzheimer’s Disease

“…The mouse model demonstrated that estradiol exerted an essential role in regulating endogenous neurogenesis, synaptic plasticity, and cognitive function in the early stage of AD [ 29 ] and protected the young APP/PS1 mice from cognitive decline [ 30 ]. In women, estrogens exert a protective role against neurodegeneration, and with the onset of menopause, the drop-in plasma level is considered a determinant factor in AD development.…”