C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Abstract

Recent work suggests that timing of 17β-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of estrogen receptor-α (ERα) in the hippocampus but not the uterus. The purpose of the current study was to determine the mechanism underlying the ERα decrease and to determine whether aging leads to a similar loss of hippocampal ERα and E2 sensitivity. The results of the study show that ERα in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the E3 ubiquitin ligase C terminus of heat shock cognate protein 70 (Hsc70)-interacting protein (CHIP) that leads to its ubiquitination/proteasomal degradation following LTED (10-wk ovariectomy). E2 treatment initiated before but not after LTED prevented the enhanced ERα-CHIP interaction and ERα ubiquitination/degradation and was fully neuroprotective against global cerebral ischemia. Administration of a proteasomal inhibitor or CHIP antisense oligonucleotides to knock down CHIP reversed the LTED-induced down-regulation of ERα. Further work showed that these observations extended to natural aging, because aged rats showed enhanced CHIP interaction; ubiquitination and degradation of both hippocampal ERα and ERβ; and, importantly, a correlated loss of E2 neuroprotection against global cerebral ischemia. In contrast, E2 administration to middle-aged rats was still capable of exerting neuroprotection. As a whole, the study provides support for a "critical period" for E2 neuroprotection of the hippocampus and provides important insight into the mechanism underlying the critical period.estradiol | neuroendocrine | steroid | stroke B asic science and clinical observation studies have provided evidence of a beneficial effect of 17β-estradiol (E2) on cardiovascular disease, neuroprotection, and neurodegenerative diseases such as stroke and Alzheimer's disease (1-6). However, the Women's Health Initiative (WHI) surprisingly failed to observe a protective effect of hormone therapy on the cardiovascular system and, in fact, reported a small but significant increase in risk for stroke and dementia (7-9). The average age of subjects in the WHI study was 63 y, far past the onset of menopause. It has been suggested that there may be a "critical period" for the beneficial protective effect of E2 on the brain and that estrogen may need to be administered at perimenopause or earlier to observe a beneficial effect on the cardiovascular and neural system (10-12). In support of a critical period hypothesis for E2 beneficial effects in the brain, work by our laboratory and others has shown that long-term E2 deprivation (LTED) leads to a loss of E2 neuroprotection in animal models of focal and global cerebral ischemia (GCI) (13,14). Intriguingly, recent work by our group showed that the loss of E2 neuroprotection of the hippocampal CA1 region, an area ...

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

“…These data also support the hypothesis that ER␤ signaling in response to E2 is drastically altered by age, as the expression levels of these proteins did not significantly correlate with changes in protein-protein interaction. In this study there were no significant changes in ER␤ protein levels with age or E2 treatment, and this is consistent with a similar report that recently demonstrated no age or E2 deprivation effects on ER␤ expression (24). E2 deprivation or replacement decreased ER␤ expression in 24-month-old but not 18-month-old rats (20 -24).…”

“…S-nitrosylation of GAPDH initiates apoptosis by translocating to the nucleus and interacting with Siah1 (an E3-ubiquitin ligase), also known as BAG-1. BAG-1 has been shown to interact with ER␣ and facilitate the down-regulation of estrogen receptors over extended periods of E2 deprivation (24). Overall, the role for a nuclear interaction between ER␤ and GAPDH is not yet clear, but a change in this interaction could dysregulate the balance between E2 neuroprotection and apoptosis in aged animals.…”

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…Other investigators have reported similarly detrimental effects of long-term ovariectomy on the ability of chronic E 2 to enhance spatial working memory , supporting the idea that long-term hormone deprivation impairs E 2 's capacity to facilitate hippocampal synaptic plasticity and memory. The reasons for this decreased responsiveness are not yet clear, but could be due to ubiquitination and degradation of estrogen receptors as observed in the CA1 of long-term ovariectomized rats (Zhang et al 2011).…”

Change in brain and lesion volumes after CEE therapies

“…25 For these women, there was no long-term effect of HT on cognition, either positive or negative. Another area of work is related to estrogen receptor binding that may explain how neuroprotective effects of estrogen may erode with aging 26,27 ; however, these do not explain why CEE therapy may adversely affect brain volumes in older women.…”