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. 2023 Aug 24;15:1223977. doi: 10.3389/fnagi.2023.1223977

FIGURE 5.

FIGURE 5

The effect of reduced ALDH2 activity and ethanol on AD pathology. Ethanol appears to affect directly tau homeostasis, increase neuroinflammation and endothelial dysfunction – all pathologies associated with AD (blue boxes). Ethanol metabolism (purple boxes) results in accumulation of acetaldehyde. Accumulation of acetaldehyde decreases activity of ALDH2 and exacerbates ROS production, lipid peroxidation and accumulation of other toxic aldehydes, such as 4HNE (orange boxes). All these further increase AD-associated pathologies (yellow boxes). Thick lines indicate pathways of exacerbation and dotted lines indicate pathways of attenuation. In humans and in knock-in mice, ALDH2 activity in wild type, ALDH2*1/*1, is 100%; ALDH2 activity in ALDH2*2/*1 (heterozygotes) is 10–45%; ALDH2 activity in ALDH2*2/*2 (homozygotes) is 2–5%. Carriers of ALDH2*2/*2 accumulate more aldehydes as indicated by the dotted pathway is the reduced ALDH2 activity. 4-HNE, 4-hydroxynonenal; 4-HNA, 4-hydroxynonenic acid; ROS, reactive oxygen species; PUFAs, polyunsaturated fatty acids; Aβ, amyloid β.