Ethanol-induced PGE2 up-regulates Aβ production through PKA/CREB signaling pathway

Gabr, A. A.; Lee, Hyun Jik; Onphachanh, Xaykham; Jung, Young Hyun; Kim, Jun Sung; Chae, Chang Woo; Han, Ho Jae

doi:10.1016/j.bbadis.2017.06.020

Cited by 14 publications

(7 citation statements)

References 60 publications

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“…As classified by the World Health Organization (WHO), alcohol use is the third-highest health risk factor in developed countries and the greatest risk factor in developing countries, [12] and its aldehydic metabolite, acetaldehyde, is classified as a class I carcinogen [36]. Relevant to our study, epidemiological studies have shown that excessive alcohol consumption is a risk factor for dementia [49] and alcohol intake drives expression levels of amyloid precursor protein (APP) and Aβ-producing enzymes in animal models [21, 27]. Alcohol also increases lipid peroxidation through increased oxidative stress and drives mitochondrial dysfunction [38, 39, 58].…”

Section: Introductionmentioning

confidence: 91%

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Joshi

Wassenhove

Logas

et al. 2019

acta neuropathol commun

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Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

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Section: Introductionmentioning

confidence: 91%

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Joshi

Wassenhove

Logas

et al. 2019

acta neuropathol commun

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“…Exacerbation of AD pathogenesis by alcohol has been reported using both in vitro and in vivo studies. In human, SK-N-MC neuroblastoma cells ethanol upregulated BACE1 expression and Aβ production, as well as increased reactive oxygen species (ROS) production, cyclooxygenase-2 (COX-2) expression and PGE 2 production [ 32 ]. Ethanol exposure of mice for 4 weeks increased APP levels and BACE1 expression, promoted Aβ production, increased plaque deposition, and worsened cognitive deficits [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…In Alzheimer’s disease (AD), microglial phagocytosis of oligomeric and aggregated forms of amyloid beta (Aβ) is one of the key means by which amyloid burden is limited [ 26 , 27 ]. Several studies suggest that alcohol may be a risk factor for AD [ 28 – 31 ], and there are also reports that alcohol increases amyloid processing and deposition [ 32 – 34 ]. However, whether alcohol influences the ability or efficacy of microglial cells to internalize Aβ has not been examined, although several studies have shown that peripheral macrophages have reduced phagocytotic activity after alcohol treatment [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis

Kalinin

González‐Prieto

Scheiblich

et al. 2018

J Neuroinflammation

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BackgroundMicroglial activation contributes to the neuropathology associated with chronic alcohol exposure and withdrawal, including the expression of inflammatory and anti-inflammatory genes. In the current study, we examined the transcriptome of primary rat microglial cells following incubation with alcohol alone, or alcohol together with a robust inflammatory stimulus.MethodsPrimary microglia were prepared from mixed rat glial cultures. Cells were incubated with 75 mM ethanol alone or with proinflammatory cytokines (“TII”: IL1β, IFNγ, and TNFα). Isolated mRNA was used for RNAseq analysis and qPCR. Effects of alcohol on phagocytosis were determined by uptake of oligomeric amyloid beta.ResultsAlcohol induced nitrite production in control cells and increased nitrite production in cells co-treated with TII. RNAseq analysis of microglia exposed for 24 h to alcohol identified 312 differentially expressed mRNAs (“Alc-DEs”), with changes confirmed by qPCR analysis. Gene ontology analysis identified phagosome as one of the highest-ranking KEGG pathways including transcripts regulating phagocytosis. Alcohol also increased several complement-related mRNAs that have roles in phagocytosis, including C1qa, b, and c; C3; and C3aR1. RNAseq analysis identified over 3000 differentially expressed mRNAs in microglia following overnight incubation with TII; and comparison to the group of Alc-DEs revealed 87 mRNAs modulated by alcohol but not by TII, including C1qa, b, and c. Consistent with observed changes in phagocytosis-related mRNAs, the uptake of amyloid beta1–42, by primary microglia, was reduced by alcohol.ConclusionsOur results define alterations that occur to microglial gene expression following alcohol exposure and suggest that alcohol effects on phagocytosis could contribute to the development of Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1184-7) contains supplementary material, which is available to authorized users.

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“…A study showed that SXFAD mice deficient in p38 α , and the knockdown of p38 α , leads to enhanced A β degradation by increasing the expression of neprilysin, a metalloproteinase in glial cells [ 94 ]. The activating transcription factor 4 (ATF4) is another factor that enables the activation of proapoptotic proteins of p38 by initiating MKK6 [ 95 ], and p38 helps in binding the Atf4 factor to the CHOP promoter and proceeds in the expression of caspase-4 [ 96 ].…”

Section: The Baseline Of Neuroinflammation In Admentioning

confidence: 99%

“…For the treatment with interferons, the Janus kinase (JAK) is essential for the phosphorylation of STAT factors [100]. The STAT members are diverse in their function and are accounted to play a crucial role in differentiation, proliferation, and cell survival [90][91][92][93][94][95][96][97][98][99][100][101][102][103]. They function as essential mediators in cytokine receptor signaling and are involved in the modulation of transcriptional target genes.…”

Section: Jak-stat Pathwaymentioning

confidence: 99%

Inflammation and Alzheimer’s Disease: Mechanisms and Therapeutic Implications by Natural Products

Rather

Khan

Alshahrani

et al. 2021

Mediators of Inflammation

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Alzheimer’s disease (AD) is a neurodegenerative disorder with no clear causative event making the disease difficult to diagnose and treat. The pathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and widespread neuronal loss. Amyloid-beta has been extensively studied and targeted to develop an effective disease-modifying therapy, but the success rate in clinical practice is minimal. Recently, neuroinflammation has been focused on as the event in AD progression to be targeted for therapies. Various mechanistic pathways including cytokines and chemokines, complement system, oxidative stress, and cyclooxygenase pathways are linked to neuroinflammation in the AD brain. Many cells including microglia, astrocytes, and oligodendrocytes work together to protect the brain from injury. This review is focused to better understand the AD inflammatory and immunoregulatory processes to develop novel anti-inflammatory drugs to slow down the progression of AD.

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Ethanol-induced PGE2 up-regulates Aβ production through PKA/CREB signaling pathway

Cited by 14 publications

References 60 publications

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis

Inflammation and Alzheimer’s Disease: Mechanisms and Therapeutic Implications by Natural Products

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