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 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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia affecting more than 50 million people globally in 2018 [13]
aldehyde dehydrogenase 2 (ALDH2)*2 mutation in Alzheimer’s disease patient-derived fibroblasts Screening 20 AD patient-derived fibroblast lines, we identified ALDH2*2/*1 carrier in one Japanese patient afflicted with Alzheimer’s disease (AG11369; onset at ~ the age of 50 years) (Fig. 1a), who had three siblings affected with dementia (AG10643, AG10644, and AG10646)
Using Alda-1, a previously characterized small molecule activator of ALDH2 that restores the activity of ALDH*2/*1 heterozygotic enzyme to Wild type (WT) levels [8], all the above defects observed in the fibroblasts of this AD patient were significantly corrected (Fig. 1e-g; Additional file 1: Figure S1C, D)
Summary
Alzheimer’s disease (AD) is the most common form of dementia affecting more than 50 million people globally in 2018 [13]. Joshi et al Acta Neuropathologica Communications (2019) 7:190 aldehydes, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) [5]. These aldehydes form stable adducts with all macromolecules, including proteins required for mitochondrial functions thereby directly inhibiting these processes [61]. 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]. Since ethanol exposure greatly increases aldehydic load [41], we hypothesized that suppression of neuroinflammation by increasing aldehyde removal may be beneficial in subjects at risk for neurodegenerative diseases, such as AD
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