The Interaction Between NF-κB and Estrogen in Alzheimer’s Disease

Mishra, Pranav; Davies, Don A.; Albensi, Benedict C.

doi:10.1007/s12035-022-03152-3

Cited by 13 publications

(14 citation statements)

References 162 publications

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“…These genes are crucial to regulate innate immune pathways, including the nuclear factor kappa‐B (NF‐κB) related Toll‐like receptor pathway, NOD‐like receptors signaling, IL‐1 signaling, and CLRs pathways (Figure 3). The previous finding has demonstrated that the sex hormone estrogen modulated NF‐κB induced neuroinflammation in AD progression 71–73 . Our finding indicates that estrogen mediates the communication between ex‐neuron and microglia in AD subjects (Figure 5B).…”

Section: Discussionsupporting

confidence: 69%

“…The previous finding has demonstrated that the sex hormone estrogen modulated NF‐κB induced neuroinflammation in AD progression. 71 , 72 , 73 Our finding indicates that estrogen mediates the communication between ex‐neuron and microglia in AD subjects (Figure 5B ). In particular, microglia in female AD subjects showed a reduction in alzPAS related to the metabolism of steroid hormones and innate immune pathways, such as CLRs pathways and IL‐6 family signaling, but no alzPAS alteration were observed in males.…”

Section: Discussionmentioning

confidence: 63%

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Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Hou,

Caldwell,

Lathia

et al. 2023

Alzheimer's & Dementia

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IntroductionThe molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.MethodsTo address this problem, we investigated cellular metabolism and immune responses (“immunometabolism endophenotype”) across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.ResultsWe identified sex‐specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female‐specific elevation in glycerophosphorylcholine and N‐acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)‐17 signaling, C‐type lectin receptor, interferon signaling, and Toll‐like receptor pathways. We pinpointed distinct microglia‐specific immunometabolism endophenotypes (i.e., lipid‐ and amino acid‐specific IL‐10 and IL‐17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate‐mediated immunometabolism.DiscussionOur results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD.HIGHLIGHTS Sex‐specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin‐10 pathway activity. Female AD subjects showed a shift in glutamate‐mediated cell‐cell communications between excitatory neurons to microglia and astrocyte.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 63%

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Hou,

Caldwell,

Lathia

et al. 2023

Alzheimer's & Dementia

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“…As previously mentioned, NF-κB regulates NO, which mediates oxidative stress and microglial activation via TLR signaling [ 85 ]. Some less studied elements of NF-κB action correlated to AD are aging control [ 86 ], estrogenic regulative action [ 87 ], and flavonoid neuroprotection [ 88 ]. WES technology showed that EGCG downregulated NF-κB, which shows a flavonoid intervention in regulating inflammatory action.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

et al. 2023

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Chronic neuroinflammation is associated with many neurodegenerative diseases, such as Alzheimer’s. Microglia are the brain’s primary immune cells, and when activated, they release various proinflammatory cytokines. Several natural compounds with anti-inflammatory and antioxidant properties, such as epigallocatechin 3-gallate (EGCG), may provide a promising strategy for inflammation-related neurodegenerative diseases involving activated microglia cells. The objective of the current study was to examine the molecular targets underlying the anti-inflammatory effects of EGCG in activated microglia cells. BV-2 microglia cells were grown, stimulated, and treated with EGCG. Cytotoxicity and nitric oxide (NO) production were evaluated. Immunoassay, PCR array, and WES™ Technology were utilized to evaluate inflammatory, neuroprotective modulators as well as signaling pathways involved in the mechanistic action of neuroinflammation. Our findings showed that EGCG significantly inhibited proinflammatory mediator NO production in LPS-stimulated BV-2 microglia cells. In addition, ELISA analysis revealed that EGCG significantly decreases the release of proinflammatory cytokine IL-6 while it increases the release of TNF-α. PCR array analysis showed that EGCG downregulated MIF, CCL-2, and CSF2. It also upregulated IL-3, IL-11, and TNFS10. Furthermore, the analysis of inflammatory signaling pathways showed that EGCG significantly downregulated mRNA expression of mTOR, NF-κB2, STAT1, Akt3, CCL5, and SMAD3 while significantly upregulating the expression of mRNA of Ins2, Pld2, A20/TNFAIP3, and GAB1. Additionally, EGCG reduced the relative protein expression of NF-κB2, mTOR, and Akt3. These findings suggest that EGCG may be used for its anti-inflammatory effects to prevent neurodegenerative diseases.

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“…The improvements in healthcare access and a concurrent rise in lifespan for the global population has resulted in an increased prevalence of neurodegenerative disorders [28,41,[73][74][75][76][77][78]. Diseases of the nervous system represent over six hundred disorders that lead to death and disability [61,76,77,79,80].…”

Section: Cellular Metabolism In the Nervous Systemmentioning

confidence: 99%

“…Long-COVID, also known as long-haul COVID, post-acute COVID-19, and chronic COVID, represents long-term effects that can occur following acute SARS-CoV-2 infection. Multiple mechanisms can account for this chronic syndrome, including metabolic pathways, apoptosis, autophagy, oxidative stress, mitochondrial dysfunction, and cytokine release [56,73,74,[86][87][88]91,177,178,180,206,212,251,[385][386][387][388][389][390][391][392][393]. With the knowledge of the role of APOE-ε4 in metabolism and autophagy signaling, APOE-ε4 has been linked to the effects of long COVID and dementia.…”

Section: Cellular Metabolism and The ε4 Allele Of The Apolipoprotein ...mentioning

confidence: 99%

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

Maiese

2023

Biomolecules

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It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

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The Interaction Between NF-κB and Estrogen in Alzheimer’s Disease

Cited by 13 publications

References 162 publications

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

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