Neuropsychiatric-like behavioural features of the Aldh2-/- mouse model of Alzheimer’s disease
Alzheimer’s disease (AD) is a complex, multifaceted neurodegenerative disorder characterized by progressive memory impairment and frequently presents with neuropsychiatric comorbidities, notably anxiety and depression. We have established Aldh2-/- mice as an oxidative stress-based model of age-related memory loss and cognitive impairment. However, very little is known about non-cognitive behavioural deficits, or if a sexual dimorphism exist in this model, as it does in humans. We performed a behavioural characterization of anxiety-related behaviours in response to aversive stimuli and depression-like behaviours related to despair and anhedonia. The performance of three cohorts at different time points (3-4, 7-8, and 11-12 months) was examined in a battery of behavioural tests consisting of an assessment of mobility and exploration (open field test), anxiety-related behaviour (light/dark box, elevated plus maze), and depression-related behaviour (forced swim test, tail suspension test, sucrose preference test). Compared to wild type mice, male and female Aldh2-/- mice exhibited increased anxiety-like behaviours that were first observed at 7 months of age. This anxious behaviour was prevented in Aldh2-/- mice treated with a deuterated polyunsaturated fatty acid (D-PUFA) diet for 10 weeks. Male Aldh2-/- mice exhibited a diminished preference for sucrose compared to wild type male mice. Dysfunction in the hypothalamic-pituitary (HPA) axis presents along with AD, anxiety, and depression. It was postulated that HPA dysfunction may underlie anxious and depressed behaviours in this model. This was evaluated using a mild chronic unpredictable stress (CUS) paradigm. The sucrose preference test and serum corticosterone analysis revealed no differences in response to chronic stress or acute stress between Aldh2-/- and wild type mice. These data reveal previously unreported behavioural abnormalities in the Aldh2-/- model of AD-like cognitive impairment.