Behavioural and Cognitive Assessment of Aldehyde Dehydrogenase 2 (Aldh2) Null Mice: a New, Oxidative Stress‐Based Model of Age‐Related Alzheimer's Disease (AD)

Abstract

The study of AD has been hindered by the absence of animal models of late-onset/age-related AD (95% of AD cases) since current transgenic mouse models exhibit pathological changes dependent on overexpression of mutant human genes linked to early-onset, familial AD (1-5% of cases). Oxidative stress is considered a causative factor in age-related AD, and ALDH2 is important for the catabolism of toxic aldehydes (eg. 4-hydroxynonenal, HNE) associated with oxidative stress-induced lipid peroxidation. Aldh2 null mice exhibit oxidative stress, many AD-like pathologies, and importantly, age-related decreases in performance in recognition and spatial memory tasks beginning at 3 months of age and maximal at 6 months. Differences in locomotor activity and coordination, as well as behavioural phenotype using the open field test, balance beam and SHIRPA standardised battery were not observed, suggesting that diminished cognitive performance was the result of impaired memory and not due to confounding changes in motor function. Additionally, chronic administration of GT1061, a neuroprotectant that targets synaptic failure via activation of NO/cGMP/pCREB signaling, and histidine hydrazide, an HNE scavenger, reverses the progressive memory deficits and biochemical changes that occur in these mice. The presence of AD-like pathologies and the reversal of memory and biochemical deficits by pharmacological intervention, suggests that Aldh2 null mice represent a new, oxidative stress-based model of age-related cognitive impairment and AD that may prove useful both for assessing AD therapeutics and for gaining better insight into the pathogenesis of AD.