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(A) Estrogen receptor structure and function. Homology between ERα and ERβ: amino acid identity (%) in the N-terminal activation function 1 region (AF-1), DNA-binding domain (DBD), hinge region (H), ligand-binding domain (LBD), and C-terminal function 2 domain (AF-2); (B) interaction of neurotrophin receptor and estrogen signaling pathways. Schematic outlining of the neurotrophin receptors and their associated peptides and a simplified diagram describing the main signaling pathways activated by the Trk and p75 receptors. Activation and subsequent phosphorylation of the Trk receptor results in the activation of the MEK/ERK signaling pathway, that leads to phosphorylation of transcription factors (TFs) like CREB and promotes cell differentiation and survival; and the PI3K/Akt pathway that promotes cell survival. The p75NTR signals modulate the NF-κB and JNK pathways, which promotes inflammation and cell survival or apoptosis respectively. The classical and non-classical estrogen pathway interacts with neurotrophin system and regulates neuronal survival and ameliorative effects on the BFCN. Dashed arrows indicate various targets.
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The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's diseas...
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Nerve growth factor (NGF) gene therapy rescues and stimulates cholinergic neurons, which degenerate in Alzheimer's disease (AD). In a recent clinical trial for AD, intraparenchymal AAV2-NGF delivery was safe but did not improve cognition. Before concluding that NGF gene therapy is ineffective, it must be shown that AAV2-NGF successfully engaged the...
Citations
... Two estrogen receptor genes have been identified in humans encoding alpha and beta receptor subtypes, ERα (ESR1) and ERβ (ESR2). They share >95% amino acid homology in their DNA-binding domains and 59% sequence identity in their ligand-binding domains [70,71]. When the ligand interacts with ERα or ERβ in the target cell, the receptors undergo a conformational change, forming homo-or heterodimers and become associated with other proteins. ...
... Two estrogen receptor genes have been identified in humans encoding al beta receptor subtypes, ERα (ESR1) and ERβ (ESR2). They share >95% amino acid ogy in their DNA-binding domains and 59% sequence identity in their liganddomains [70,71]. When the ligand interacts with ERα or ERβ in the target cell, th tors undergo a conformational change, forming homo-or heterodimers and becom ciated with other proteins. ...
The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology.
... However, as AD progresses, the degeneration of AChproducing cholinergic neurons becomes more widespread, and the efficacy of treatment declines as the availability of the appropriate substrate diminishes [151]. Estrogen receptors also colocalize with tropomyosin-related kinase receptor A (TrkA), tropomyosin-related kinase receptor B (TrkB), and neurotrophin receptors (NR) in basal cholinergic neurons of the forebrain (BFCN) [152]. TrkA binds to nerve growth factor (NGF) and TrkB binds to brain-derived neurotrophic factor (BDNF). ...
... This NR/growth factor system plays a critical role in the survival, differentiation, and repair of these neurons. By altering estrogen levels, NR expression also changes, with estrogen depletion resulting in rapid reductions in the number of receptors [152,153]. Ovariectomized rats' estrogenic treatment leads to upregulation of BDNF mRNA expression in the cortex and olfactory bulbs (which are connected to BFCN through afferent innervation) and provides neurotrophic support for these neurons [154]. The increase in BDNF expression by estrogen therapy will also positively impact neurogenesis [155][156][157], an important event negatively affected by aging and disease conditions such as in AD [154,157]. ...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for more than half of all dementia cases in the elderly. Interestingly, the clinical manifestations of AD disproportionately affect women, comprising two thirds of all AD cases. Although the underlying mechanisms for these sex differences are not fully elucidated, evidence suggests a link between menopause and a higher risk of developing AD, highlighting the critical role of decreased estrogen levels in AD pathogenesis. The focus of this review is to evaluate clinical and observational studies in women, which have investigated the impact of estrogens on cognition or attempted to answer the prevailing question regarding the use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS, and PubMed (keywords "memory", "dementia," "cognition," "Alzheimer's disease", "estrogen", "estradiol", "hormone therapy" and "hormone replacement therapy" and by searching reference sections from identified studies and review articles). This review presents the relevant literature available on the topic and discusses the mechanisms, effects, and hypotheses that contribute to the conflicting findings of HRT in the prevention and treatment of age-related cognitive deficits and AD. The literature suggests that estrogens have a clear role in modulating dementia risk, with reliable evidence showing that HRT can have both a beneficial and a deleterious effect. Importantly, recommendation for the use of HRT should consider the age of initiation and baseline characteristics, such as genotype and cardiovascular health, as well as the dosage, formulation, and duration of treatment until the risk factors that modulate the effects of HRT can be more thoroughly investigated or progress in the development of alternative treatments can be made.
... [25] PI3K/Akt and Ras-MEK-MAPK pathways are reported to be the key mechanisms of neurotrophin-induced survival. [26] The aggregation of Aβ 42 activates different astrocyte and microglial cell receptors, inducing the production of ROS and numerous proinflammatory cytokines (TNF-α and IL-1β), all of which consequently stimulate MAPK signaling pathways. Oxidative stress activates JNK and p38 and induces β secretase gene expression, whereas β-secretase gene expression is negatively regulated by ERK1/2. ...
... The basal forebrain contains the largest number of cholinergic neurons in the forebrain. BFCNs are involved in many cognitive functions, including attention, learning and memory, and are particularly vulnerable in AD [74]. The main outcome of the pathogenesis of AD is the destruction of cholinergic pathways in the cerebral cortex and basal forebrain [34]. ...
Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.
... The non-genomic response, also called the non-classical pathway, which does not involve ERE transcription factors, acts much faster than the genomic response. It usually responds within seconds because signals are mediated by the G-protein-coupled receptor and kinases [209]. There are four estrogen-binding membrane receptors, include G-protein-coupled estrogen receptor (GPER), Gq-coupled membrane estrogen receptor (Gq-mER), membrane subpopulation of ERs (mERα/β), and ER-X [210]. ...
The impacts of menopause on neurodegenerative diseases, especially the changes in steroid hormones, have been well described in cell models, animal models, and humans. However, the therapeutic effects of hormone replacement therapy on postmenopausal women with neurodegenerative diseases remain controversial. The steroid hormones, steroid hormone receptors, and downstream signal pathways in the brain change with aging and contribute to disease progression. Estrogen and progesterone are two steroid hormones which decline in circulation and the brain during menopause. Insulin-like growth factor 1 (IGF-1), which plays an import role in neuroprotection, is rapidly decreased in serum after menopause. Here, we summarize the actions of estrogen, progesterone, and IGF-1 and their signaling pathways in the brain. Since the incidence of Alzheimer’s disease (AD) is higher in women than in men, the associations of steroid hormone changes and AD are emphasized. The signaling pathways and cellular mechanisms for how steroid hormones and IGF-1 provide neuroprotection are also addressed. Finally, the molecular mechanisms of potential estrogen modulation on N-methyl-d-aspartic acid receptors (NMDARs) are also addressed. We provide the viewpoint of why hormone therapy has inconclusive results based on signaling pathways considering their complex response to aging and hormone treatments. Nonetheless, while diagnosable AD may not be treatable by hormone therapy, its preceding stage of mild cognitive impairment may very well be treatable by hormone therapy.
... For example, estrogen has been shown to not only enhance the non-amyloidogenic cleavage of APP by increasing the expression of α-secretase, but also facilitates the clearance of Aβ by promoting its phagocytosis by microglia [7]. Moreover, estrogen appears to have the ability to reduce tau aggregates and stimulate the expression of choline acetyltransferase (ChAT) in the basal forebrain, thereby slowing the cognitive decline caused by AD [8]. However, other factors may also contribute to the pathophysiology of AD, such as mitochondrial dysfunction, oxidative stress, neurotransmitter failure, and inflammation [9,10]. ...
... The mouse model of OVX used in the present study showed clearly atrophic changes in the uterus, a decrease in the circulating level of E2, and cognitive deficits in a manner that may be reversed by HRT with 17β-estradiol. These results are consistent with previous findings from ours and other groups [8,10,14,16], indicating that the animal model prepared was appropriate for mimicking the estrogen-depleted state of females and elucidating the pharmacological activities of drugs, including natural herbal medicines such as PM. ...
... The activation of estrogen receptors has been linked to PI3K and MAPK signaling pathways, which play important roles in neurogenesis, synaptic plasticity, and ERK1/2 signaling. Furthermore, facilitation of the ERK1/2 signaling system via estrogen receptors reportedly leads to a decrease in β-amyloid production [8]. Many studies have reported that chronic neuroinflammation in the brain increases the risk for AD [28]. ...
The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17β-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17β-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1β, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.
... The increase of ROS generation via Cd intoxication in two types of neuronal cell lines, PC12 and SH-SY5Y (Yuan et al. 2016), leads to the involvement of mTOR (rapamycin) and the MAPK (mitogen-activated protein kinase) ways in mammalians. Cd intoxication also causes blockage of calcium channels (Choong et al. 2014;Chouchene et al. 2016;Kwakowsky et al. 2016;Lichtenfels et al. 2017;Mladenović et al. 2014;Saroj et al. 2017;Zhou et al. 2015). ...
Heat shock proteins (HSPs) are a family of proteins that are expressed by cells in reply to stressors. The changes in concentration of HSPs could be utilized as a bio-indicator of oxidative stress caused by heavy metal. Exposure to the different heavy metals may induce or reduce the expression of different HSPs. The exposure to cadmium ion (Cd²⁺) could increase HSP70 and HSP27 over 2- to 10-fold or even more. The in vitro and in vivo models indicate that the HSP70 family is more sensitive to Cd intoxication than other HSPs. The analyses of other HSPs along with HSP70, especially HSP27, could also be useful to obtain more accurate results. In this regard, this review focuses on examining the literature to bold the futuristic uses of HSPs as bio-indicators in the initial assessment of Cd exposure risks in defined environments.
Graphical abstract
... [25] PI3K/Akt and Ras-MEK-MAPK pathways are reported to be the key mechanisms of neurotrophin-induced survival. [26] The aggregation of Aβ 42 activates different astrocyte and microglial cell receptors, inducing the production of ROS and numerous proinflammatory cytokines (TNF-α and IL-1β), all of which consequently stimulate MAPK signaling pathways. Oxidative stress activates JNK and p38 and induces β secretase gene expression, whereas β-secretase gene expression is negatively regulated by ERK1/2. ...
Alzheimer’s disease (AD) is classified as an age‑related neuro‑degenerative disorder leading to loss of memory and decline in
cognitive abilities, often characterized as dementia. According to the WHO report 2020, out of 50 million people battling with
dementia worldwide, 60%–70% cases account for AD. Some researchers have reported two to three times higher incidence of
AD among women than men and further confirmed that postmenopausal women are more prone to AD than healthy men of the
same age. This hints at the potential neuroprotective role of estrogen hormone, whose level drops to <30 pg/mL postmenopause.
Several epidemiological studies also suggest early postmenopausal use of estrogens may contribute to the prevention, attenuation,
or even delay in the onset of AD. Collectively, this evidence supports the further development of estrogen‑like compounds for
the treatment and prevention of AD, with a rising interest in phytoestrogens as potential interventions with lower side effects.
This review highlights multiple pathways of estrogen‑mediated neuroprotection against neurodegenerative diseases like AD
and discusses the role of selective estrogen receptor molecules mainly phytoestrogens, in AD progression so that latter can be
considered and used as an alternate therapy for treating Alzheimer patients.
... 1,2 The reduction of circulating estrogen level with menopause may modify age-related cognitive changes and may accelerate typical aging. 3,4 Estrogens have been observed to be involved in a number of neuroprotective roles, from modulating cholinergic function at the basal forebrain, 5 to interacting with neurofibrillary tau tangles in preclinical Alzheimer disease (AD) models. 6 Therefore, the loss of these mechanisms after menopause due to depletion of cortical estrogens is believed to be a driving factor behind the increased risk of women developing AD compared to men. 7 Thus, the present study investigated whether the endorsement of cognitive complaints after menopause was associated with objective cognition and cortical structure. ...
Objective:
Menopause is associated with increasing cognitive complaints and older women are at increased risk of developing Alzheimer disease compared to men. However, there is difficulty in early markers of risk using objective performance measures. We investigated the impact of subjective cognitive complaints on the cortical structure in a sample of younger postmenopausal women.
Methods:
Data for this cross-sectional study were drawn from the baseline visit of a longer double-blind study examining estrogen-cholinergic interactions in normal postmenopausal women. Structural Magnetic Resonance Imaging was acquired on 44 women, aged 50-60 years and gray-matter volume was defined by voxel-based morphometry. Subjective measures of cognitive complaints and postmenopausal symptoms were obtained as well as tests of verbal episodic and working memory performance.
Results:
Increased levels of cognitive complaints were associated with lower gray-matter volume in the right medial temporal lobe (r = -0.445, P < 0.002, R = 0.2). Increased depressive symptoms and somatic complaints were also related to increased cognitive complaints and smaller medial temporal volumes but did not mediate the effect of cognitive complaints. In contrast, there was no association between performance on the memory tasks and subjective cognitive ratings, or medial temporal lobe volume.
Conclusions:
The findings of the present study indicate that the level of reported cognitive complaints in postmenopausal women may be associated with reduced gray-matter volume which may be associated with cortical changes that may increase risk of future cognitive decline. : Video Summary:http://links.lww.com/MENO/A626.
... Polymers 2020, 12, 1506 2 of 10 the risk of breast and ovarian cancer in women [5]. Some other diseases are related to this hormone, such as bladder cancer [6] and Alzheimer's disease [7,8]. Mammals secrete this hormone and its derivatives daily through urine, which reach the wastewater in addition to remnants from the pharmaceutical industry. ...
Novel potentiometric devices “ion-selective electrodes (ISEs)” were designed and characterized for the detection of 17β-estradiol (EST) hormone. The selective membranes were based on the use of man-tailored biomimics (i.e., molecularly imprinted polymers (MIPs)) as recognition ionophores. The synthesized MIPs include a functional monomer (methacrylic acid (MAA)) and a cross-linker (ethylene glycol dimethacrylic acid (EGDMA)) in their preparation. Changes in the membrane potential induced by the dissociated 17β-estradiol were investigated in 50 mM CO32−/HCO3− buffer solution at pH 10.5. The ion-selective electrodes (ISEs) exhibited fast response and good sensitivity towards 17β-estradiol with a limit of detection 1.5 µM over a linear range starts from 2.5 µM with an anionic response of 61.2±1.2 mV/decade. The selectivity pattern of the proposed ISEs was also evaluated and revealed an enhanced selectivity towards EST over several phenolic compounds. Advantages revealed by the presented sensor (i.e., wide range of assay, enhanced accuracy and precision, low limit of detection, good selectivity, long-term potential stability, rapid response and long life-span and absence of any sample pretreatment steps) suggest its use in routine quality control/quality assurance tests. They were successfully applied to estradiol determination in biological fluids and in different pharmaceutical preparations collected from the local market.
