Association Between Aldehyde dehydrogenase-2 Polymorphisms and Risk of Alzheimer's Disease and Parkinson's Disease: A Meta-Analysis Based on 5,315 Individuals

Huang, Wei; Cheng, Chao-Hui; Zhou, Lan; Jiang, Guang-Bin; Hu, Yuanyuan

doi:10.3389/fneur.2019.00290

Cited by 31 publications

(29 citation statements)

References 43 publications

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“…AD and PD (Chen et al, 2019;Joshi et al, 2019). Even though the growing body of literature suggests the potential neuroprotective effects of low to moderate dose of ethanol, factors such as genetic variation in metabolism of ethanol should be further explored in its role of neuroinflammation and neurodegeneration.…”

Section: Alcohol: Could It Be Neuroprotective?mentioning

confidence: 99%

“…In reality, most of the alcohol dependent patients practice episodic drinking pattern with more than one type of alcoholic drinks, therefore assessment of the effects of any specific types of alcohol containing drinks on their cognitive performance or neurological features is nearly impossible. In addition, rate of alcohol metabolism also varies among the individuals and impairment in metabolism of aldehydes (one of the by-products of ethanol metabolism) due to mutation in aldehyde dehydrogenase 2 (ALDH2) was identified as a risk factor for AD and PD ( Chen et al, 2019 ; Joshi et al, 2019 ). Even though the growing body of literature suggests the potential neuroprotective effects of low to moderate dose of ethanol, factors such as genetic variation in metabolism of ethanol should be further explored in its role of neuroinflammation and neurodegeneration.…”

Section: Aud-induced Neurodegenerative Diseasementioning

confidence: 99%

See 1 more Smart Citation

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Kamal

Tan

Ibrahim

et al. 2020

Front. Cell. Neurosci.

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Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer's and Parkinson's disease.

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Section: Alcohol: Could It Be Neuroprotective?mentioning

confidence: 99%

Section: Aud-induced Neurodegenerative Diseasementioning

confidence: 99%

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Kamal

Tan

Ibrahim

et al. 2020

Front. Cell. Neurosci.

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“…Despite the unpleasant reaction to acetaldehyde accumulation, 17–27% of individuals with this ALDH2 mutation consume alcoholic beverages excessively; up to 3 drinks per day or 7 drinks per week for women and up to 4 drinks per day or no more than 14 drinks per week for men [3]. Additionally, a recent meta-analysis correlated ALDH2*2 genotype and AD development; six case-control studies involving 2840 subjects indicated an increased risk of the ALDH2*2 genotype for AD [10].…”

Section: Introductionmentioning

confidence: 99%

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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“…Earlier findings from our group and others indicated a beneficial role for ALDH2 in cardiovascular diseases, including diabetes mellitus, ischemia reperfusion injury, atherosclerosis, stroke, sepsis, and obesity, through regulation of autophagy. 21 , 30 – 32 , 59 , 60 In the context of neurodegenerative diseases, ALDH2 deficiency was reported to be correlated with AD incidence, 23 , 25 although contradictory findings were noted, disproving the correlation between ALDH2 and AD risk in humans. 28 , 34 , 61 The possible role for ALDH2 in AD pathology is consistent with low ALDH2 activities in AD patients and APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy

Wang

Qin

et al. 2020

Sig Transduct Target Ther

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Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2 −/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.

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Association Between Aldehyde dehydrogenase-2 Polymorphisms and Risk of Alzheimer's Disease and Parkinson's Disease: A Meta-Analysis Based on 5,315 Individuals

Cited by 31 publications

References 43 publications

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

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

ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy

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