ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer’s disease process

Liu, Junying; Yuan, Shouli; Niu, Xinhui; Kelleher, Robbie; Sheridan, Helen

doi:10.18632/aging.204359

Cited by 9 publications

(4 citation statements)

References 74 publications

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“… 43 Besides, its abnormal expression has been associated with symptoms of AD. 44 While ESR1 and ESR2 genes are associated with increased risk of AD, 45 MAOB elevation is a characteristic of AD. 46 Furthermore, higher BChE activity is reported with AD.…”

Section: Resultsmentioning

confidence: 99%

Tinospora cordifolia Extract Enhances Dextromethorphan Bioavailability: Implications for Alzheimer’s Disease

Majhi,

Sayyad,

Gaur

et al. 2024

ACS Omega

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Tinospora cordifolia (Willd.) Miers (Menispermaceae) is a traditional rejuvenator and a conventional medicine used to manage oxidative stress-related diseases, including those associated with the central nervous system. Decreased dextromethorphan (DEM) metabolism is necessary for high bioavailability and application against Alzheimer’s disease (AD). Since T. cordifolia stem extract (TCE) can potentially inhibit several metabolic enzymes, it can also enhance dextromethorphan bioavailability. This study investigates the potential of TCE to improve DEM’s bioavailability and efficacy for the management of AD. In silico analysis was carried out to find the inhibition potential of phytocomponents of T. cordifolia for CYP2D6 and CYP3A4. The LC-MS method was revalidated for the analysis of DEM and metabolite dextrorphan (DEX) in the presence of quinidine (QN). The ratio of DEM to DEX was estimated with varying doses of TCE following pharmacokinetic analysis. Network pharmacology analysis was carried out to understand the complementary potential of phytocomponents. This was further validated in the scopolamine-induced dementia model through behavioral and histopathological analyses. TCE (100 mg/kg) for 14 days increased the DEM to DEX ratio by 2.8-fold compared to QN treatment. While T max was comparable to that of QN treatment at this dose (100 mg/kg) of TCE, it increased significantly at the higher dose (400 mg/kg) of TCE pretreatment. All other pharmacokinetic parameters were also enhanced at this dose with a 4.7-fold increase in DEM/DEX compared with QN. Network pharmacology analysis indicated the ability of TCE to target multiple factors associated with AD. Furthermore, it improved spatial memory and reduced hyperactivity in rodents better than the combination of QN and DEM.

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Section: Resultsmentioning

confidence: 99%

Tinospora cordifolia Extract Enhances Dextromethorphan Bioavailability: Implications for Alzheimer’s Disease

Majhi,

Sayyad,

Gaur

et al. 2024

ACS Omega

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“…The dysfunction of ESR1 will lead to neuroinflammation and further increase the risk of Alzheimer's disease. Apolipoprotein E (APOE) can regulate the activity of ESR1 through CEBPB/ATF, mir-155-5p, and mir-1-3p [55]. Peroxisome proliferator-activated receptor (PPAR receptor) belongs to the nuclear receptor proteins, and is mainly involved in the regulation of transcription factor expression.…”

Section: Discussionmentioning

confidence: 99%

Study of the Anti-Inflammatory Mechanism of β-Carotene Based on Network Pharmacology

Wu,

Chen,

Chen

et al. 2023

Molecules

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β-carotene is known to have pharmacological effects such as anti-inflammatory, antioxidant, and anti-tumor properties. However, its main mechanism and related signaling pathways in the treatment of inflammation are still unclear. In this study, component target prediction was performed by using literature retrieval and the SwissTargetPrediction database. Disease targets were collected from various databases, including DisGeNET, OMIM, Drug Bank, and GeneCards. A protein–protein interaction (PPI) network was constructed, and enrichment analysis of gene ontology and biological pathways was carried out for important targets. The analysis showed that there were 191 unique targets of β-carotene after removing repeat sites. A total of 2067 targets from the three databases were integrated, 58 duplicate targets were removed, and 2009 potential disease action targets were obtained. Biological function enrichment analysis revealed 284 biological process (BP) entries, 31 cellular component (CC) entries, 55 molecular function (MF) entries, and 84 cellular pathways. The biological processes were mostly associated with various pathways and their regulation, whereas the cell components were mainly membrane components. The main molecular functions included RNA polymerase II transcription factor activity, DNA binding specific to the ligand activation sequence, DNA binding, steroid binding sequence-specific DNA binding, enzyme binding, and steroid hormone receptors. The pathways involved in the process included the TNF signaling pathway, sphingomyelin signaling pathway, and some disease pathways. Lastly, the anti-inflammatory signaling pathway of β-carotene was systematically analyzed using network pharmacology, while the molecular mechanism of β-carotene was further explored by molecular docking. In this study, the anti-inflammatory mechanism of β-carotene was preliminarily explored and predicted by bioinformatics methods, and further experiments will be designed to verify and confirm the predicted results, in order to finally reveal the anti-inflammatory mechanism of β-carotene.

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“…A phytoSERM that contains genistein, daidzein, and S -equol and preferentially targets ERβ was found to preserve cognitive function in women with genetic risk modulators for AD, i.e., mitochondrial haplogroup and APOE genotype [ 45 ]. A functional link between ER signaling and AD could rely on APOE-mediated modulation of ESR1 that involves CEBPB/ATF4, miR-155-5p, or miR-1-3p [ 46 ]. Therefore, the cited studies confirm the rationale for undertaking our research; however, they do not indicate the exclusive participation of non-nuclear ER signaling pathways in neuroprotection against AD as our present study does.…”

Section: Discussionmentioning

confidence: 99%

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

Pietrzak-Wawrzyńska,

Wnuk,

Przepiórska-Drońska

et al. 2023

Mol Neurobiol

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Targeting the non-nuclear estrogen receptor (ER) signaling has been postulated as novel therapeutic strategy for central nervous system pathologies. Recently, we showed that newly designed PaPE-1 (Pathway Preferential Estrogen-1), which selectively activates ER non-nuclear signaling pathways, elicited neuroprotection in a cellular model of Alzheimer’s disease (AD) when it was applied at the same time as amyloid-β (Aβ). Since delayed treatment reflects clinical settings better than cotreatment does, current basic study proposes a novel therapeutic approach for AD that relies on a posttreatment with PaPE-1. In this study, mouse neuronal cell cultures treated with preaggregated Aβ1-42 (10 µM) showed the presence of extracellular Aβ1-42, confirming the adequacy of the AD model used. We are the first to demonstrate that a 24-h delayed posttreatment with PaPE-1 decreased the degree of Aβ-induced neurodegeneration, restored neurite outgrowth, and inhibited the expression of AD-related genes, i.e., Rbfox, Apoe, Bace2, App, and Ngrn, except for Chat, which was stimulated. In addition, PaPE-1 elicited anti-apoptotic effects by inhibiting Aβ-induced caspase activities as well as attenuating apoptotic chromatin condensation, and in these ways, PaPE-1 prevented neuronal cell death. Posttreatment with PaPE-1 also downregulated the Aβ-affected mRNA expression of apoptosis-specific factors, such as Bax, Gsk3b, Fas, and Fasl, except for Bcl2, which was upregulated by PaPE-1. In parallel, PaPE-1 decreased the protein levels of BAX, FAS, and FASL, which were elevated in response to Aβ. PaPE-1 elicited a decrease in the BAX/BCL2 ratio that corresponds to increased methylation of the Bax gene. However, the PaPE-1-evoked Bcl2 gene hypermethylation suggests other PaPE-1-dependent mechanisms to control Aβ-induced apoptosis.

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ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer’s disease process

Cited by 9 publications

References 74 publications

Tinospora cordifolia Extract Enhances Dextromethorphan Bioavailability: Implications for Alzheimer’s Disease

Tinospora cordifolia Extract Enhances Dextromethorphan Bioavailability: Implications for Alzheimer’s Disease

Study of the Anti-Inflammatory Mechanism of β-Carotene Based on Network Pharmacology

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

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