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

ABSTRACT: 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 ?4 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-?, 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 A?, 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.

SUBMITTER: Joshi AU

PROVIDER: S-EPMC6907112 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Joshi Amit U AU Van Wassenhove Lauren D LD Logas Kelsey R KR Minhas Paras S PS Andreasson Katrin I KI Weinberg Kenneth I KI Chen Che-Hong CH Mochly-Rosen Daria D

Acta neuropathologica communications 20191212 1

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 ...[more]

PMID: 31829281

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

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

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