Aldehyde dehydrogenase-2 modulates acrolein toxicity to promote neural repair after spinal cord injury

Oxidative stress-derived aldehydes, particularly acrolein, are key mediators of secondary damage following spinal cord injury. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is a key oxidoreductase responsible for detoxifying reactive aldehydes, but its activity is markedly reduced in individuals carrying the ALDH2*2 variant. In this study, we used a transgenic ALDH2*2 mouse model to investigate the role of ALDH2 in the pathology of spinal cord injury. This model mimics the human ALDH2*2 condition, allowing us to examine the impact of impaired aldehyde clearance on acrolein accumulation and its pathological consequences. We modulated endogenous aldehyde detoxification through both genetic deficiency and pharmacological activation with a selective agonist, Alda-1. Our results showed that ALDH2 deficiency led to significantly elevated acrolein levels, which were associated with increased microglial activation, cytokine storm, neuronal loss, demyelination, and tissue damage compared with wild-type mice. Treatment with Alda-1 enhanced ALDH2 activity and significantly reduced acrolein levels in both ALDH2*2 and wild-type mice from 2 to 28 days post-spinal cord injury. This was accompanied by reduced inflammation, improved preservation of myelin, and marked improvements in locomotor and sensory function, especially in ALDH2*2 mice. Notably, even beyond the traditionally ideal treatment window, Alda-1 treatment remained effective in promoting recovery, particularly in motor function and to a greater extent in ALDH2*2 mice. Our study comprehensively evaluated ALDH2's role in spinal cord injury by both genetically impairing and pharmacologically enhancing its activity, highlighting ALDH2 as a critical modulator of acrolein-mediated damage and suggesting its potential as a therapeutic target, especially for individuals with the ALDH2*2 mutation.