Estrogen deficiency induces memory loss via altered hippocampal HB-EGF and autophagy

Abstract

Estrogen deficiency reduces estrogen receptor-alpha (ERα) and promotes apoptosis in the hippocampus, inducing learning-memory deficits; however, underlying mechanisms remain less understood. Here, we explored the molecular mechanism in an ovariectomized (OVX) rat model, hypothesizing participation of autophagy and growth factor signaling that relate with apoptosis. We observed enhanced hippocampal autophagy in OVX rats, characterized by increased levels of autophagy proteins, presence of autophagosomes and inhibition of AKT-mTOR signaling. Investigating upstream effectors of reduced AKT-mTOR signaling revealed a decrease in hippocampal heparin-binding epidermal growth factor (HB-EGF) and p-EGFR. Moreover, 17β-estradiol and HB-EGF treatments restored hippocampal EGFR activation and alleviated downstream autophagy process and neuronal loss in OVX rats. In vitro studies using estrogen receptor (ERα)-silenced primary hippocampal neurons further corroborated the in vivo observations. Additionally, in vivo and in vitro studies suggested the participation of an attenuated hippocampal neuronal HB-EGF and enhanced autophagy in apoptosis of hippocampal neurons in estrogen- and ERα-deficient conditions. Subsequently, we found evidence of mitochondrial loss and mitophagy in hippocampal neurons of OVX rats and ERα-silenced cells. The ERα-silenced cells also showed a reduction in ATP production and an HB-EGF-mediated restoration. Finally in concordance with molecular studies, inhibition of autophagy and treatment with HB-EGF in OVX rats restored cognitive performances, assessed through Y-Maze and passive avoidance tasks. Overall, our study, for the first time, links neuronal HB-EGF/EGFR signaling and autophagy with ERα and memory performance, disrupted in estrogen-deficient condition.

PIP 2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

“…Importantly, HB-EGF, which we previously reported is able to restore functional hyperemia in SVD mice (13), also increased ATP levels and reestablished normal Kir current density in SVD cECs. As a mitogenic factor, HB-EGF has previously been shown to increase cytosolic ATP concentrations (32,33), and expression of its cognate receptor (EGFR) in the brain vascular endothelium is high compared with that in other vascular beds (34). Despite the potential for EGFR-dependent activation of phospholipase C (35), our data and the literature support the concept that EGFR activation in SVD cECs enhances mitochondrial function, which acts presumably by increasing intracellular ATP levels to stimulate PI4/PIP5 kinase-mediated PIP 2 formation and restore normal Kir2.1 function.…”

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

“…To the best of our knowledge, such an effect has not been previously reported in APOE4 mice, but the effect of menopause has been observed in OVX models. [82][83][84] mTOR activation, likely triggered via the PI3K-AKT pathway, is critical for neuronal cell survival, and is intriguingly associated with maintenance of glucose homeostasis, with similar deficits established in the diabetic rat brain, 85 thus highlighting potential metabolic/bioenergetic disturbances in the APOE4 VCDtreated brain. Furthermore, AKT and mTOR activation in AD mouse models ameliorates deficits in synaptic plasticity improving associated learning and memory.…”

Improvement of Cognitive Function in Ovariectomized Rats by Human Neural Stem Cells Overexpressing Choline Acetyltransferase via Secretion of NGF and BDNF

“…Estrogen deficiency during menopause induces diverse abnormal symptoms, including osteoporosis and weight gain [ 3 , 29 ]. In particular, it induces apoptosis, neuronal loss, and cognitive dysfunction in the hippocampus [ 30 ]. Therefore, several studies have focused on developing therapeutic strategies, such as hormone replacement, and understanding their mechanisms [ 31 , 32 , 33 ].…”