Protective Effects of G Protein-Coupled Estrogen Receptor 1 (GPER1) on β-Amyloid-Induced Neurotoxicity: Implications for Alzheimer’s Disease

Kurt, Akif Hakan; Yüksel, Kasım Zafer; Üremiş, Nuray; Uremis, Muhammed Mehdi; Altun, İdiris; Boşnak, Mehmet; Kılıçaslan, Derya; Alli, Bilge

doi:10.1134/s1819712419010148

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…Recently, an experimental study conducted with rat cortex cells tested the effect in different situations of neurotoxicity. The authors showed that G-1 increased cell survival, which suggests that early activation of GPER1 may improve therapeutics in neurodegeneration [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression and miRNA–Gene Interactions in Early and Late Mild Cognitive Impairment

Brito

Ribeiro-dos-Santos

Vidal

et al. 2020

Biology

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Mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) are complex diseases with their molecular architecture not elucidated. APOE, Amyloid Beta Precursor Protein (APP), and Presenilin-1 (PSEN1) are well-known genes associated with both MCI and AD. Recently, epigenetic alterations and dysregulated regulatory elements, such as microRNAs (miRNAs), have been reported associated with neurodegeneration. In this study, differential expression analysis (DEA) was performed for genes and miRNAs based on microarray and RNA-Seq data. Global gene profile of healthy individuals, early and late mild cognitive impairment (EMCI and LMCI, respectively), and AD was obtained from ADNI Cohort. miRNA global profile of healthy individuals and AD patients was extracted from public RNA-Seq data. DEA performed with limma package on ADNI Cohort data highlighted eight differential expressed (DE) genes (AGER, LINC00483, MMP19, CATSPER1, ARFGAP1, GPER1, PHLPP2, TRPM2) (false discovery rate (FDR) p-value < 0.05) between EMCI and LMCI patients. Previous molecular studies showed associations between these genes with dementia and neurological-related pathways. Five dysregulated miRNAs were identified by DEA performed with RNA-Seq data and edgeR (FDR p-value < 0.002). All reported miRNAs in AD interact with the aforementioned genes. Our integrative transcriptomic analysis was able to identify a set of miRNA–gene interactions that may be involved in cognitive and neurodegeneration processes.

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Section: Discussionmentioning

confidence: 99%

Differential Expression and miRNA–Gene Interactions in Early and Late Mild Cognitive Impairment

Brito

Ribeiro-dos-Santos

Vidal

et al. 2020

Biology

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“…Single-onset traumatic brain injury is also associated with acute neuronal loss in the hippocampus, and G1 can ameliorate early-onset cognitive deficits and neuronal death by activating the PI3K/Akt pathway ( Wang et al, 2017 ). G1 also significantly mitigates Aβ1-42-induced neuronal toxicity ( Kurt et al, 2019 ) and alleviates the impairment of novel object recognition memory in female 5XFAD mice ( Kubota et al, 2016 ).…”

Section: The Effects Of Gper On Memory Impairmentmentioning

confidence: 99%

The effects of GPER on age-associated memory impairment induced by decreased estrogen levels

Luo

Yan

Cao

et al. 2023

Front. Mol. Biosci.

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Estrogen, as a pleiotropic endocrine hormone, not only regulates the physiological functions of peripheral tissues but also exerts vital neuroregulatory effects in the central nervous system (CNS), such as the development of neurons and the formation of neural network connections, wherein rapid estrogen-mediated reactions positively stimulate spinogenesis and regulate synaptic plasticity and synaptic transmission to facilitate cognitive and memory performance. These fast non-genomic effects can be initiated by membrane-bound estrogen receptors (ERs), three best known of which are ERα, ERβ, and G protein-coupled estrogen receptor (GPER). To date, the effects of ERα and ERβ have been well studied in age-associated memory impairment, whereas there is still a lack of attention to the role of GPER in age-associated memory impairment, and there are still disputes about whether GPER indeed functions as an ER to enhance learning and memory. In this review, we provide a systematic overview of the role of GPER in age-associated memory impairment based on its expression, distribution, and signaling pathways, which might bring some inspiration for translational drugs targeting GPER for age-related diseases and update knowledge on the role of estrogen and its receptor system in the brain.

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“…The neuroprotective contribution of GPER1 in AD has been highlighted in the rodent AD models ( 103 ). GPER1 inhibits Aβ-induced oxidative stress and neuronal cell death in rat neuronal cells ( 104 ). Moreover, GPER1 has been observed to stimulate extracellular signal-regulated kinase (ERK) signaling in rat hippocampal neurons, leading to activation of synaptic NMDA receptors and trafficking of AMPA receptors into hippocampal synapses, which in turn causes a persistent increase in synaptic efficacy, suggesting a role for GPER1 in modulating neuronal plasticity in neurodegenerative diseases, including AD ( 105 ).…”

Section: Er Function In the Brain And Association With Admentioning

confidence: 99%

Expression and function of estrogen receptors and estrogen-related receptors in the brain and their association with Alzheimer’s disease

2023

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While estrogens are well known for their pivotal role in the female reproductive system, they also play a crucial function in regulating physiological processes associated with learning and memory in the brain. Moreover, they have neuroprotective effects in the pathogenesis of Alzheimer’s disease (AD). Importantly, AD has a higher incidence in older and postmenopausal women than in men, and estrogen treatment might reduce the risk of AD in these women. In general, estrogens bind to and activate estrogen receptors (ERs)-mediated transcriptional machineries, and also stimulate signal transduction through membrane ERs (mERs). Estrogen-related receptors (ERRs), which share homologous sequences with ERs but lack estrogen-binding capabilities, are widely and highly expressed in the human brain and have also been implicated in AD pathogenesis. In this review, we primarily provide a summary of ER and ERR expression patterns in the human brain. In addition, we summarize recent studies on their role in learning and memory. We then review and discuss research that has elucidated the functions and importance of ERs and ERRs in AD pathogenesis, including their role in Aβ clearance and the reduction of phosphorylated tau levels. Elucidation of the mechanisms underlying ER- and ERR-mediated transcriptional machineries and their functions in healthy and diseased brains would provide new perspectives for the diagnosis and treatment of AD. Furthermore, exploring the potential role of estrogens and their receptors, ERs, in AD will facilitate a better understanding of the sex differences observed in AD, and lead to novel sex-specific therapeutic approaches.

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Protective Effects of G Protein-Coupled Estrogen Receptor 1 (GPER1) on β-Amyloid-Induced Neurotoxicity: Implications for Alzheimer’s Disease

Cited by 3 publications

References 36 publications

Differential Expression and miRNA–Gene Interactions in Early and Late Mild Cognitive Impairment

Differential Expression and miRNA–Gene Interactions in Early and Late Mild Cognitive Impairment

The effects of GPER on age-associated memory impairment induced by decreased estrogen levels

Expression and function of estrogen receptors and estrogen-related receptors in the brain and their association with Alzheimer’s disease

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