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 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.

Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication

“…The regulation of GABA synthesis by astrocytic ALDH2 may have an impact on many common neurological diseases other than ethanol use disorder. ALDH2 deficiency has been found to contribute to aging 50 , anxiety 51 , nociceptive state 52 and addiction mechanisms 9,53 . Additionally, astrocytic GABA synthesis and release has been linked with Alzheimer's disease pathology [54][55][56] .…”

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

“…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.…”

“…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.…”

A common East Asian-specific ALDH2 mutation causes obesity and insulin resistance: therapeutic effect of reducing toxic aldehydes by ALDH2 activation

“…Plasmid construction, expression and puri cation of human ALDH2 in Escherichia coli E. coli BL21 (DE3) was transformed with pTrcHi-WT ALDH2 and pTrcHi -KI ALDH2 29 . The transformants were cultured and then induced to express recombinant proteins using 0.4 mM IPTG for 16-18 hours at 25 °C.…”

“…Aldh2 KI mice carrying the human ALDH2 Glu504Lys mutation were generated by introducing the Glu504Lys mutation within the mouse gene 29 . Both Aldh2 WT controls and Aldh2 KI mice were littermates from mated heterozygous mice.…”