MID-LIFE COMPLEX AND NOVEL ENVIRONMENTAL ENRICHMENT INCREASE CORTICOSTERONE AND EXACERBATE AB NEUROPATHOLOGY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE

Abstract

Background: The biggest risk factor for Alzheimer’s disease (AD) is advancing age, however modifiable factors such as level of education and job complexity are also associated with dementia risk. Complex cognitive activity has the potential to promote an array of neuroplastic alterations, and the ageing brain also has capacity to benefit from engaging in complex mental tasks. On the other hand, a high cognitive demand can induce stress. Findings from epidemiological studies have revealed that lifestyle factors, including stress, modulate the progression of AD. Methods: In this study we examined the effect of environmental enrichment (EE) initiated in mid-life in a transgenic (Tg) AD mouse model (APP/PS1) and healthy wildtype (Wt) mice. At 6 months of age, when the Tg mice have established Aβ plaque pathology, mice were randomly assigned to one of three different housing conditions for 6 months. Mice were randomly allocated to standard housing (SH), EE (toys, tunnels, running wheel, larger exploratory space), or EE+. Mice assigned to EE+ were housed in EE, however also entered a novel environment weekly. Following the 6-month differential housing period, we analysed the effect of environmental stimulation on Aβ pathological burden and blood corticosterone levels. Results: Tg AD mice housed in EE+ showed increased Aβ plaque pathology (M = 2.70%) compared to SH (M = 1.51%) or EE (M = 1.98%) mice (p = .02). In addition, they had significantly increased blood corticosterone levels (ng/mL) (SH M = 124.59; EE M = 133.03; EE+ M = 216.29, p = .01). Interestingly, the Tg EE+ mice demonstrated no significant cognitive differences to those in SH or EE despite increases in Aβ pathology and the stress marker corticosterone. In addition, healthy Wt mice in EE+ did not show this pattern of heightened corticosterone. Conclusions: Our data suggest that long-term complex environmental stimulation introduced later in life induces stress and exacerbates existing Aβ neuropathology in AD. The findings indicate that this kind of chronic stress may be a significant contributing factor in the development and progression of AD, particularly for those susceptible to the disease.