The study of Alzheimer’s Disease (AD) has been hindered by the absence of animal models of late-onset/age-related AD (also termed sporadic 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 (5% of cases). Oxidative stress is considered to be a causative factor in age-related AD, and we have found that aldehyde dehydrogenase 2 (Aldh2) null mice exhibit not only oxidative stress, but also display many AD-like pathologies. The current study used behavioral analysis to assess whether Aldh2-/- mice also exhibit memory and cognition deficits. Male and female wild type and Aldh2-/- mice were tested monthly beginning at three months of age, using the open field novel object recognition test (a measure of recognition memory), as well as spontaneous alternations in the Y-maze (a measure of spatial working memory). In both tasks, significant decreases in performance occurred in Aldh2-/- mice by 3.5-4 months of age, and this progressively declined over the next three months compared to wild type mice. Sex-related differences in memory impairment were not observed. These results, together with the findings that AD-like pathologies are also present, suggest that Aldh2-/- mice represent a new, oxidative stress-based model of age-related cognitive impairment and AD. This model may prove useful both for assessing AD therapeutics and for gaining better insight into the pathogenesis of AD. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2013-09-26 11:20:00.023

Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat myocardial ischemia and congestive heart failure. GTN is proposed to act as a prodrug that requires bioactivation for pharmacological activity. However, continuous administration results in tolerance development, limiting its clinical usefulness. Aldehyde dehydrogenase 2 (ALDH2) has been proposed to be the primary enzyme responsible for GTN bioactivation, and ALDH2 inactivation has been proposed as the sole basis of nitrate tolerance. In the present study, we utilized an in vivo GTN tolerance model to investigate the role of ALDH2 in GTN bioactivation and tolerance. We assessed changes in ALDH2 protein, mRNA and activity levels in rat blood vessels during chronic GTN exposure (0.4 mg/hr for 6, 12, 24 and 48 hr) in relation to changes in vasodilator responses to GTN. A time-dependent decrease in both ALDH2 expression and activity occurred (80% in tolerant veins and 30% in tolerant arteries after 48 hrs exposure to GTN), concomitant with decreased vasodilator responses to GTN. However, after a 24 hr drug-free period following 48 hr GTN exposure, the vasodilator responses to GTN had returned to control values, whereas ALDH2 expression and activity were still markedly depressed. The dissociation between reduced ALDH2 activity and expression, and the duration of the impaired vasodilator responses to GTN in nitrate-tolerant blood vessels, suggest factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2008-10-03 16:14:49.313