Role of Dickkopf-1, an Antagonist of the Wnt/β-Catenin Signaling Pathway, in Estrogen-Induced Neuroprotection and Attenuation of Tau Phosphorylation

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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 ...

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Zhang

Han

Wang

et al. 2011

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“…Intriguingly, the higher risk and poorer outcome of stroke in postmenopausal women parallels the falling E2 levels that occur after menopause (7,8). Furthermore, exogenous administration of E2 significantly reduces the infarct volume in cortex and hippocampus after focal and global cerebral ischemia (GCI) in various animal models, and female animals exhibit reduced neural damage compared with young adult males after brain injury (1,(9)(10)(11). Taken as a whole, these studies suggest E2 functions as an important neuroprotective factor.…”

mentioning

confidence: 88%

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Sareddy

Zhang

Wang

et al. 2015

17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/ β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.he steroid hormone, 17β-estradiol (E2), exerts multiple actions in the brain, including regulation of synaptic plasticity, neurogenesis, reproductive behavior, and cognition. E2 has also been implicated to serve as an important neuroprotective factor in a variety of neurodegenerative disorders, including stroke and Alzheimer's disease (1-3). The main source of E2 synthesis in females is the ovary. Circulating E2 levels are known to fluctuate during development and puberty, as well as during the menstrual cycle. After menopause, however, circulating E2 levels decline precipitously (4). Relative to men, women are "protected" against stroke until the years of menopause. However, after menopause, women exhibit a significantly higher disability and fatality rate compared with men (5-7). Intriguingly, the higher risk and poorer outcome of stroke in postmenopausal women parallels the falling E2 levels that occur after menopause (7,8). Furthermore, exogenous administration of E2 significantly reduces the infarct volume in cortex and hippocampus after focal and global cerebral ischemia (GCI) in various animal models, and female animals exhibit reduced neural damage compared with young adult males after brain injury (1, 9-11). Taken as a whole, these studies suggest E2 functions as an important neuroprotective factor. However, the molecular mechanisms by which E2 exerts its neuroprotective effects remain unclear.E2 signaling is thought to be primarily mediated by the classical...

“…Crosstalk and synergy between ERα signaling and the WNT pathways have been described (24)(25)(26). In the brain, estrogen signaling activates WNT by down-regulating dickkopf-1 (Dkk1), a WNT antagonist, to prevent neurodegeneration (27). In the uterus, estrogen prompts the canonical WNT signaling pathway in the uterine epithelium to induce uterine epithelial cell growth (28), and in breast cancer, ERα activation enhances cell growth via WNT signaling (29).…”

mentioning

confidence: 99%

The bone-sparing effects of estrogen and WNT16 are independent of each other

Movérare‐Skrtic

Henning

et al. 2015

Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16 −/− mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. OblWnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L 3 . Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx OblWnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16 −/− mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16 −/− and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.WNT16 | estrogen | cortical bone | trabecular bone | transgenic mice B oth estrogen and wingless-type MMTV integration site family (WNT)16 are crucial regulators of bone mass in women (1-5). The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα) (6). Estrogen-deficiency leads to rapid bone loss and contributes significantly to the development of postmenopausal osteoporosis that can be prevented by estradiol treatment. However, this treatment is associated with side effects such as breast cancer and thromboembolism (7,8).The WNTs are a family of secreted glycoproteins that consists of 19 members in mammals, and which mediates autocrine and paracrine effects by binding to frizzled (Fzd) receptors and LDL-related protein 5/6 (LRP5/6) coreceptors (9). During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signaling is critical in bone development and in the regulation of adult bone homeostasis (10-20) and modulation of WNT signaling has emerged as a promising strategy for increasing bone mass (21-23). Crosstalk and synergy between ERα signaling and the WNT pathways have been described (24-26). In the brain, estrogen signaling activates WNT by down-regulating dickkopf-1 (Dkk1), a WNT antagonist, to pr...